Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH2:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31]>CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:36]([C:35]3[CH:37]=[CH:38][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CCc1ccc(N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Yield: 30.6 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (1.0 molar, 0.7 ml) and 4-ethylaniline (0.093 g) to give the desired 8-(2-chloro-benzenesulfonyl)-2-(4-ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.068 g) as a light-brown solid. MS (ESI): 433.136 (MH+).
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31](O)[CH3:32].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CC(O)CN(C)C
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)OC(C)CN(C)C

Procedure:
1-Dimethylamino-2-Propyl Tributylstannyl Ether is prepared from 89.4 gm (0.15 mole) bis(tributyltin) oxide and 30.9 gm (0.3 mole) 1-dimethylamino-2-propanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing 23 hours a total of 2.6 ml of water (theory 2.7 ml) had collected in the Dean-Starke tube. The solvent is stripped off on a rotating evaporator to provide 111.0 gm of yellow liquid. This is fractionated at reduced pressure with collection at 167°-175° C. at 0.5 mm of 63.4 gm of straw colored liquid. (Percent yield - 54). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)=[O:13])[N:6]=[CH:5]2.Cl[C:21]1[C:22]2[N:23]([CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:25][N:26]=1>C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:21]3[C:22]4[N:23]([CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:25][N:26]=3)[CH2:16]1)=[O:13])[N:6]=[CH:5]2
Reactant: Clc1nccn2cccc12
Reactant: O=C(N[C@H]1CCNC1)c1ncc2cc(Cl)ccc2n1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc2cc(Cl)ccc2n1
Temperature: 90 °C
Yield: 6 %

Procedure:
To a solution of the crude amine in 0.16 mL of diisopropylethylamine was added 1-chloropyrrolo[1,2-a]pyrazine (0.047 g, 0.31 mmol) followed by 1 drop of 1-butyl-3-methylimidazolium tetrafluorborate. The reaction was heated at 90° C. for 20 h. Purification of the residue by HPLC afforded (S)-6-chloro-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)quinazoline-2-carboxamide (0.05 g, 0.013 mmol, 6%). 1H NMR (400 MHz, CD3OD) δ 9.60 (s, 1 H), 8.26(s, 1 H), 8.17 (d, J=9.1 Hz, 1 H), 8.07 (dd, J=1.8, 9.1 Hz, 1 H), 7.76 (d, J=1.5 Hz, 1 H), 7.72 (d, J=5.8 Hz, 1 H), 7.57 (s, 1 H), 6.93 (m, 1 H), 6.85 (d, J=5.8 Hz, 1 H), 5.06-4.84 (m, 1 H), 4.82-3.60 (br, 4 H), 2.65-2.40 (br, 2 H); MS: (ES) m/z calculated for C20H17ClN6O [M+H]+ 393.2, found 393.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][N:7]=1.[NH2:20][OH:21]>C(O)C.O>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:20][OH:21])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C#N)c2)cnc1N
Reactant: NO
Solvent: O
Solvent: CCO
Product: CNC(=O)c1nc(-c2cccc(C(=N)NO)c2)cnc1N
Temperature: 25 °C
Yield: 71.6 %

Procedure:
3-Amino-6-(3-cyanophenyl)-N-methylpyrazine-2-carboxamide (155 mg, 0.61 mmol) was suspended in ethanol (2 mL) followed by addition of 50% aqueous hydroxylamine (250 uL, 4.1 mmol) and the mixture was heated to reflux for 30 minutes then allowed to cool to room temperature. The suspension was diluted with water (2 mL) and the solid product collected by filtration and dried in vacuo to give crude 3-amino-N-methyl-6-{3-[(hydroxyamino)(imino)methyl]phenyl}pyrazine-2-carboxamide (125 mg, 72% yield) as a yellow solid which was carried forward without further purification: MS (EI) for C13H15N6O2: 287 (MH+).
Reaction SMILES: [CH3:1][S:2][CH3:3].[K].ClC1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C)C=O>C(OCC)C>[CH3:1][S:2][C:3]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9](=[CH:15][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Cl)cc1C(=O)OCC
Reactant: CSC
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(SC)cc1C(=O)OCC

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH:11][CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(Cl)=[O:20]>O>[I:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:19](=[O:20])[N:11]([CH3:12])[C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CNc1ccc(I)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(I)ccc21
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a mechanically stirred solution of 5-iodo-N-methylanthranilic acid (40 grams 0.144 mol), potassium carbonate (19.95 grams, 0.144 mol), and 500 ml water at 0° C. was added phosgene (1.93M solution in toluene, 0.2 mol, 104 mL) over a period of 1 hr. the resulting slurry was stirred for an additional 3 hrs and the solids isolated by filtration, washing with water, and a small amount (70 mL) of ether. The solids were dried overnight in vacuo to yield 34 grams (78%) of 5-iodo-N-methylisatoic anhydride. 1H NMR (DMSO-d6) 8.18 (1H, bs, C6-H), 8.08 (1H, bd, 3JHH =8 Hz, C4-H), 7.12 (1H, d, 3JHH =8 Hz, C3-H), 3.42 (3H, s, NCH3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CBr
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.4 %

Procedure:
To a 0° C. solution of a solution of COMPOUND 249 (150 mg, 0.483 mmol) in CH2Cl2 (10 mL) and DIPEA (0.170 mL, 0.966 mmol) was added methyl bromoacetate (0.055 mL, 0.579 mmol), and the reaction mixture was stirred for 17 hr at room temperature. Saturated NaHCO3 (10 mL) was added to the reaction mixture, which was then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by radial chromatography on silica gel (20:1:0.5 CH2Cl2:MeOH:NH4OH) to give {4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-acetic acid methyl ester (154 mg, 83%). 1H NMR (CDCl3) δ 1.86-1.92 (m, 4H), 1.98-2.07 (m, 2H), 2.08 (s, 6H), 2.45-2.50 (m, 1H), 2.96-2.99 (m, 2H), 3.17 (s, 2H), 3.71 (s, 3H), 3.83 (s, 4H), 7.07 (dd, 2H, J=4.8, 7.5 Hz), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.8 Hz).
Reaction SMILES: [OH:1][CH: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.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:21]=[C:20](Cl)[N:19]=1>CN(C=O)C.CO>[Cl:17][C:18]1[N:19]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[C:22]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:23]=1
Reactant: CN(C)Cc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(Cl)nc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (44.2 mg, 0.219 mmol) in DMF (0.7 mL) was added sodium hydride (13.2 mg, 0.329 mmol). After stirring for 30 minutes, 1-(2,6-dichloropyridin-4-yl)-N,N-dimethylmethanamine (45 mg, 0.22 mmol) was added to the reaction vial. The reaction solution was heated at 100° C. overnight. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product. LCMS (M+H)+: 370.1.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:66]([N:73]1[C:77]2[CH:78]=[CH:79][C:80]([CH2:82]O)=[CH:81][C:76]=2[N:75]=[CH:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1(C)C=CC=CC=1>[CH2:66]([N:73]1[C:77]2[CH:78]=[CH:79][C:80]([CH2:82][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:6][CH:7]4[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:8]4=[O:32])=[CH:33][CH:34]=3)=[CH:81][C:76]=2[N:75]=[CH:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc2c(c1)ncn2Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: O=C1SC(Cc2ccc(OCc3ccc4c(c3)ncn4Cc3ccccc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
A mixture of 822 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 454 mg of azodicarbonyldipiperidine, 6 ml of dehydrated toluene and 0.44 ml of tributylphosphine was stirred for 30 minutes at room temperature. At the end of this time, 349 mg of 1-benzyl-5-benzimidazolemethanol were added to the reaction mixture and then the mixture was stirred for 3 hours, after which it was allowed to stand for 10 days at room temperature. The solvent was then removed by distillation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a gradient elution method, with mixtures of ethyl acetate and hexane in ratios ranging from 3:1 to 1:0 by volume as the eluent, to give 0.32 g of the title compound, softening at 90°-91° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24]([CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25].CCCCCC>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][C:24]([NH:23][C:17]2[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])=[O:25])[CH2:28][CH2:29]1
Reactant: OC(CBr)C1COc2ccccc2O1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Solvent: CCCCCC
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)C2COc3ccccc3O2)CC1
Yield: 106.6 %

Procedure:
1-(1,4-Benzodioxan-2-yl)-2-bromoethanol (formula H) (12 g) prepared according to J. Med. Chem. 13, 169, (1970), is treated with 1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine (14 g) in 500 ml of ethanol. The remainder of the procedure is described in Example 1 above and 21 g of the 1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine is obtained from hexane. The dihydrochloride salt has a melting point of 175°-176° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.O>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.C(#N)C>[CH:24]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][O:6][CH:7]3[C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)[CH2:26][CH2:25]1
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Reactant: OB(O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: c1cc(C2CC2)c2c(c1)C(C1=NCCN1)OCC2
Temperature: 120 °C

Procedure:
The mixture of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 11, 0.15 g), sodium carbonate (0.27 g), bis(triphenylphosphine)palladium(II) chloride (0.02 g), cyclopropylboronic acid (0.09 g), water (1 ml), and acetonitrile (2 ml) was heated in a microwave oven at 120° C. for 15 min. The title compound was purified with separation methods A and G. (Yield 8 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CCO>[Br:16][C:14]1[N:15]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][CH:13]=1
Reactant: Brc1csc(Br)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Brc1csc(N2CCOCC2)n1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
To a microwave vial was added N,N-diisopropylethylamine (0.86 ml, 4.9 mmol), 2,4-dibromothiazole (1.00 g, 4.1 mmol), and morpholine (0.43 ml, 4.9 mmol) in EtOH (4 mL). The mixture was heated under microwave irradiation at 140° C. for 35 minutes. The reaction mixture was concentrated in vacuo. The crude material was dissolved in minimal DCM/MeOH and purified via MPLC (eluting with 0-30% EtOAc in hexnaes) to yield 4-(4-bromothiazol-2-yl)morpholine (0.700 g, 68% yield) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-])=O.O.[NH4+].[Cl-]>C1COCC1.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[C:19]([F:22])([F:20])[F:21])=[N:8][CH:9]=1
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(Oc2ccc(N)cn2)c(C(F)(F)F)c1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 4-[(5-nitro-2-pyridinyl)oxy]-3-(trifluoromethyl)benzonitrile (Intermediate 120, 83 mg) in THF (3 mL)/water (1.5 mL) was added at room temperature, iron (75 mg, 1.34 mmol) and NH4Cl (72 mg, 1.34 mmol) and the resulting reaction mixture was stirred overnight. The mixture was filtered through a small pad of celite washing with EtOAc and water. To the filtered mixture was added an aqueous NaHCO3 saturated solution and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were dried and evaporated to dryness. The crude was purified by flash chromatography (companion system, 2×12 g Si cartridge, from 100:0 to 70:30 Cyclohexane/EtOAc) to afford the title compound (72 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33](C)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:30]1([S:27]([O:16][CH2:15][CH2:14][O:13][C:12]2[CH:17]=[CH:18][C:9]([B:4]3[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)(=[O:29])=[O:28])[CH:36]=[CH:35][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(OCCOS(=O)(=O)c3ccccc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Into dichloromethane 100 ml, 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanol (4.4 g, 16.7 mmol) synthesized in Example 2 (2b) was dissolved, to which triethylamine (4.6 ml, 33.2 mmol), 4-dimethylaminopyridine (400 mg, 3.3 mmol), tosyl chloride (4.8 g, 25.2 mmol) were sequentially added while cooling with ice. The resulting mixture was warmed back to room temperature, followed by further stirring for two hours. The resulting reaction liquid was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (6.1 g, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](S(C3C=CC=CC=3)=O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1([Mg]Cl)C=CC=CC=1.[N+:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:36]([C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:39][CH:38]=3)[OH:37])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-methoxy-4-(phenylsulfinyl)quinoline (0.232 g, 0.819 mmol) in THF (6 mL) at −78° C. was added phenylmagnesium chloride (2.0 M in THF)(0.819 ml, 1.64 mmol). After 5 min, the solution was warmed to RT for 15 minutes. The solution was then cooled to −78° C. and 4-nitrobenzaldehyde (0.371 g, 2.46 mmol) was added in one portion. After 5 min, the solution was warmed to RT. After 1 hr at RT, the reaction was quenched with saturated NH4Cl. The mixture was diluted with CH2Cl2 and washed with water and brine. The organic fraction was dried with Na2SO4 and concentrated in vacuo. The yellow residue was purified by silica gel chromatography using 20-100% Hexanes:EtOAc to afford (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol as a white solid. MH+=311.2@1.44 min
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5].FC(F)(F)S(O)(=O)=O.[CH3:29][C:30]([CH3:32])=[CH2:31].[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][C:30]([CH3:32])([CH3:31])[CH3:29])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(C)(C)C
Yield: 19.9 %

Procedure:
A solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methyl-benzophenone (3.0 g; 9.6 mmol) in 50 ml of methylenechloride is cooled down to -70° C., trifluoromethanesulfonic acid (0.3 ml) is added, then a stream of 2-methylpropene (5.5 g; 100 mmol) is introduced within 4 hours. Triethylamine (1.2 ml) is added, the temperature goes up to 20° C. The solution is shaken twice with diluted sodium hydroxide and the solventis evaporated. The residue is purified chromatographically (flash column with 30 g of silicagel, elution with toluene/acetone 20:1 (v/v)). The residue is treated with petrolether to give 0.7 g of white crystals (20% y); mp. 102° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].CN1CCOCC1>C(Cl)Cl>[C:26]1([O:25][C:23]([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:21][CH2:20]2)=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCNCC2)c1C
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(C(=O)Oc3ccccc3)CC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-piperazin-1-yl-pyridazine (60 mg, 0.21 mmol) and phenyl chloroformate (40 mg, 0.26 mmol) in CH2Cl2 (3 mL) at 25° C. is added N-methyl morpholine (0.07 mL, 0.60 mmol). After being stirred at 25° C. for 3 h, the mixture is diluted with CH2Cl2 (10 mL), and washed with saturated sodium bicarbonate (1 mL) and water (2×5 mL). The organic layer is concentrated and purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid phenyl ester (69 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1.CC(C)=[O:18].O.S([O-])(O[O-])(=O)=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([S:8]([CH2:9][CH2:10][C:11]([CH3:12])([OH:13])[CH3:14])=[O:18])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: CC(C)(O)CCSc1cc(Br)cnc1N
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(O)CCS(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 4-[(2-amino-5-bromopyridin-3-yl)thio]-2-methylbutan-2-ol (83 mg, 0.28 mmol) in a mixture of methanol (750 μL), acetone (750 μL) and water (450 μL) was added potassium peroxymonosulfate (131 mg, 0.21 mmol) and the reaction mixture was stirred for 90 minutes at 0° C. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (35% to 80% ethyl acetate in hexane) gave 4-[(2-amino-5-bromopyridin-3-yl)sulfinyl]-2-methylbutan-2-ol (52 mg, 60%); MS (EI) for C10H15BrN2O2S: 308 (MH+).