Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:11]([CH:13]1[O:15][CH2:14]1)Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[O:15]1[CH2:14][CH:13]1[CH2:11][N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1
Reactant: O=c1[nH]nc2ccccn12
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(CC2CO2)nc2ccccn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
After dissolving 2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (CAS 6969-71-7) (1.0 g) and epibromohydrin (1.27 ml) in N,N-dimethylformamide (10 ml), sodium hydride (60% in oil) (326 mg) was added and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained solid was washed with n-heptane to obtain the title compound (290 mg).
Reaction SMILES: [OH:1][C:2]1([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CO>C1COCC1>[OH:1][C:2]1([C:8]2[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: N#Cc1cccc(C2(O)CCOCC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cccc(C2(O)CCOCC2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.8 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-carbonitrile (ca. 18.9 mmol) was dissolved in anhydrous THF (80 mL) and a 1 M solution of BH3 in THF (95 mL, 95 mmol) added. The solution was stirred at ambient temperature for 2.5 hours, then quenched with methanol. The solution was adjusted to pH 1 by addition of 2 N hydrochloric acid solution and then neutralised to pH 5 with a 5 N solution of sodium hydroxide. Extraction with dichloromethane was followed by addition of further 2 N sodium hydroxide to the aqueous phase until the pH reached 14. This phase was twice extracted with dichloromethane and these combined extracts were evaporated to give a yellow gum. The aqueous extracts were acidified with 2 N hydrochloric acid and concentrated to dryness to yield a white residue. Three triturations of this residue with methanol and concentration of the methanolic liquors yielded a second crop of yellow gum. Drying in vacuo gave the title compound (2.51 g, 64%) as a foamy yellow solid; NMR δH (400 MHz, DMSO) 8.53 (1H, br s), 7.85 (1H, t, J 7.8 Hz), 7.62 (1H, d, J 7.8 Hz), 7.34 (1H, d, J 7.5 Hz), 5.75 (1H, s), 3.72 (4H, m), 3.16 (2H, s), 2.29 (2H, m), 1.42 (1H, d, J 12.3 Hz); LC-MS Retention time 0.43 min, (M+H)+ 209.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.N12CCCN=C1CCCCC2>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: OCC1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(CO)CC2)nn1

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide (0.200 g, 0.90 mmol) in 1,4-dioxane (10 mL) was added 4-piperidine methanol (0.155 g, 1.40 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL, 2.700 mmol) and tetrabutyl ammonium bromide (0.032 g, 0.10 mmol). The resulting mixture was stirred at reflux for 18 hours. 1,4-Dioxane was removed in vacuo and the obtained crude product was used without further purification.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:53])[CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([S:31]([N:34](CC4C=CC(OC)=CC=4OC)[C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)(=[O:33])=[O:32])[CH:27]=3)[CH2:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:53])[CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([S:31]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)(=[O:32])=[O:33])[CH:27]=3)[CH2:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN(c2ccc(F)cc2)S(=O)(=O)c2ccc3c(c2)CCN(CC(=O)c2ccc(C(C)(C)C)cc2)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)CN2CCc3cc(S(=O)(=O)Nc4ccc(F)cc4)ccc3C2)cc1
Reaction time: 2 h

Procedure:
Anisole (3 mL) was added to a solution of 2-[2-(4-tert-butylphenyl)-2-oxoethyl]-N-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (258 mg) in chloroform (5 mL), and the mixture was cooled in ice. Trifluoroacetic acid (1 mL) was added thereto and the mixture was stirred at the same temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added thereto and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→3:2) to afford the title compound as a pale yellow amorphous substance (153 mg).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C.Cl>C(#N)C.CCOC(C)=O>[OH:29][C:17]1[C:16]([CH2:15][CH:14]=[C:13]([CH3:36])[CH2:12][N:11]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[C:24]([O:25][CH3:26])[C:23]([CH3:27])=[C:22]2[C:18]=1[C:19](=[O:28])[O:20][CH2:21]2
Reactant: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)S(C)(=O)=O)OCC
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(CCP(=O)(O)O)S(C)(=O)=O)C(=O)OC2
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
A solution of [2-(methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonic acid diethyl ester (18 mg, 0.029 mmol) in acetonitrile (0.5 mL) was stirred with TMSBr (38 μL, 0.29 mmol) and 2,6-lutidine (34 μL, 0.29 mmol) for 2 hours at room temperature. The reaction was worked up by addition of EtOAc and aqueous 1N HCl. The organic layer was washed with brine and the solvent was removed in vacuo. The residue was suspended in a solution of 10% TFA-CH2Cl2 for 10 minutes before it was dried to provide 9.9 mg of the desired product (73%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.76 (s, 3H), 1.76-1.88 (m, 2H), 2.10 (s, 3H), 2.87 (s, 3H), 3.24-3.35 (m, 2H), 3.39 (d, 2H, J=7 Hz), 3.65 (s, 2H), 3.75 (s, 3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; 31P (121.4 MHz, DMSO-d6) δ 21.4 ppm; MS (m/z) 464.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][N:18]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 6-(4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (15 g), 3,4-dihydro-2H-pyran (24 mL) and p-toluenesulfonic acid monohydrate (3.0 g) in THF (400 mL) was stirred at r.t. until the reaction was complete. Water was added and the mixture was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed over a short path column (heptane/ethyl acetate gradient). The product containing fractions were combined, concentrated, and the resulting residue was triturated with ether to give 11 g (57%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[C:4]([O:14]C)[C:3]=1[C:16]1[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:18][CH:17]=1.FC1C=CC=C(OC)C=1C1N=NC(N(C)C2CC(C)(C)NC(C)(C)C2)=C(C2C=NN(C)C=2)C=1.B(Br)(Br)Br.Cl>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([C:16]2[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]3[CH2:24][C:25]([CH3:31])([CH3:32])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)=[CH:18][CH:17]=2)=[C:4]([OH:14])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: COc1cc(-c2cnn(C)c2)cc(F)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: BrB(Br)Br
Agent: COc1cccc(F)c1-c1cc(-c2cnn(C)c2)c(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(c1ccc(-c2c(O)cc(-c3cnn(C)c3)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h
Yield: 15 %

Procedure:
A mixture of 6-(2-fluoro-6-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine and 6-(2-fluoro-6-methoxyphenyl)-N-methyl-4-(1-methyl-1H-pyrazol-4-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (0.03 g, 0.07 mmol, total amount of the 2 regioisomers) was dissolved in CH2Cl2 (0.2 M). A 1 M solution of BBr3 in CH2Cl2 (0.3 mL, 3.5 mmol) was rapidly added. The reaction mixture was stirred for 3 h. MeOH was added to the reaction at 0° C. then the solvent was concentrated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (15 to 45% acetonitrile in water, 5 mM ammonium hydroxide as modifier). The solvent was concentrated in vacuo and the resulting solid was suspended in CH3CN/H2O (4/1 mL). 1 M aqueous HCl (3 equivalents) was added and the volatiles were concentrated in vacuo to afford the hydrochloride salt of 3-fluoro-2-(6-(methyl (2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol as a yellow solid (5 mg, 15%). LCMS Rt=0.50 min [Method Q]; [M+H]: 439.4; 1H NMR (400 MHz, DMSO) δ 9.20 (d, J=12.0 Hz, 1H), 8.29 (d, J=12.0 Hz, 1H), 8.23 (s, 1H), 8.04 (d, J=9.5 Hz, 1H), 7.92 (s, 1H), 7.79 (bs, 1H), 7.09 (dd, J=12.0, 1.5 Hz, 1H), 7.04 (s, 1H), 4.92 (bs, 1H), 3.88 (s, 3H), 3.03 (s, 3H), 2.05 (t, J=13.0 Hz, 2H), 1.81 (dd, J=13.0, 3.5 Hz, 2H), 1.53 (s, 6H), 1.49 (s, 6H).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:16]O)[CH:9]=[C:10]([F:15])[C:11]=1[N+:12]([O-:14])=[O:13].CO.C([O-])(O)=O.[Na+]>CCOCC>[Br:2][CH2:16][C:8]1[CH:9]=[C:10]([F:15])[C:11]([N+:12]([O-:14])=[O:13])=[C:6]([F:5])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(CO)cc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])c1c(F)cc(CBr)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of PBr3 (7.04 mL, 73 mmol) in Et2O (200 mL) is added under argon at 0° C. a solution of (3,5-difluoro-4-nitro-phenyl)-methanol (9.3 g, 48.7 mmol) in Et2O (200 mL). The reaction mixture was allowed to warm to 25° C. and stirred for 24 h at 25° C. After the addition of MeOH (5 mL) at 0° C., the reaction mixture was poured onto cold aq. NaHCO3 solution and the product was extracted with EtOAc. Combined organic extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after filtration through a plug of silicagel with hexane-EtOAc 3:1 as a yellow solid: TLC (hexane-EtOAc 3:1) Rf=0.40; HPLC RtA=2.01 min; 1H NMR (400 MHz, CDCl3): δ 7.14 (d, 2H), 4.40 (s, 2H).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=O)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:32]=[C:31]([NH2:33])[N:30]([CH3:34])[N:29]=2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:32]=[C:31]([NH:33][CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=3)[N:30]([CH3:34])[N:29]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2ccc(Cl)cc2)cc1NCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using {2-[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid synthesized in Example 3 and 3-(4-chlorophenyl)-1-methyl-1H-pyrazole-5-amine as starting materials and by operations similar to those of Example 242-1 and Example 242-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1) to give the title compound.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[CH2:5].C(=O)(O)[O-].[Na+].C1C(=O)N([Br:33])C(=O)C1.[Na]>C1COCC1>[Br:33][CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5]
Reactant: C=C(O[Si](C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Dissolve the title compound from Step A above (6.0 g, 20 mmol) in THF (120 mL), cool to 0° C. and add sodium bicarbonate. To the resulting suspension was added NBS and the mixture stirred for 1.5 h. TLC showed no starting material left. Poured reaction into sat'd aqueous sodium buicarbonate solution (200 mL) and extracted with ether (2×200 mL). The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The resulting product (6.4 g, 99%) was used without further purification for the next reaction. ESI-MS calculated for C12H20BrNO3: Exact Mass: 305.06. Found: 305.15 (M)+ and 307.09 (M+2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].Cl[Sn]Cl.C(C1C=CC(C(N2CCCCC2)=O)=C([N+]([O-])=O)C=1)C.Cl[S:41]([C:44]1[C:52]2[C:48](=[N:49][S:50][N:51]=2)[CH:47]=[CH:46][CH:45]=1)(=[O:43])=[O:42]>O>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[C:2]([NH:1][S:41]([C:44]2[C:52]3=[N:51][S:50][N:49]=[C:48]3[CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH:7]=1)[CH3:9]
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: CCc1ccc(C(=O)N2CCCCC2)c(N)c1
Agent: CCc1ccc(C(=O)N2CCCCC2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Product: CCc1ccc(C(=O)N2CCCCC2)c(NS(=O)(=O)c2cccc3nsnc23)c1

Procedure:
To a stirred solution of 2-nitro-4-vinylbenzoic acid piperidine amide (100 mg, 0.39 mmol) in methanol (15 mL) was added Pd on carbon (10 wt %, 25 mg). The reaction mixture was maintained under ˜1 atm H2 and stirred for 12 h. The mixture was filtered through Celite® and concentrated in vacuo to yield (4-ethyl-2-nitro-phenyl)-piperidin-1-yl-methanone, which was subsequently reduced to (2-amino-4-ethyl-phenyl-piperidin-1-yl-methanone with SnCl2.2 H2O as described in EXAMPLE 5. The title compound was prepared from the aniline (90 mg, 0.39 mmol) and 4-chlorosulfonyl-2,1.3-benzothiadiazole (181 mg, 0.78 mmol), and purified as described in EXAMPLE 15. TLC (silica gel, 3:1 EtOAc/hexanes): Rf=0.32. MS (ESI): m/z 431 [M+H]+, 453 [M+Na]+. HPLC (reversed-phase): RT=9.52 min (single peak). 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.95 (s, 1H), 8.21 (m, 2H), 7.65 (dd, J=8.8 Hz, 7 Hz, 1H), 7.47 (d, J=1.3 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H) 6.85 (dd, J=7.9 Hz, 1.6 Hz, 1H), 3.14 (bs, 4H), 2.60 (m, 2H), 1.61 (m, 2H), 1.43 (bs, 4H), 1.17 (t, J=7.6 Hz, 3H). Elemental analysis: calculated for C20H22N4O3S2, C, 55.79; H, 5.15; N, 13.01. found C, 55.44; H, 5.50; N, 12.62.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:21])[CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Reactant: C=O
Solvent: C1CCOC1
Product: CN1CCC(N(C)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.1 %

Procedure:
To a solution of (S)-3-(1-methyl-piperidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.35 mmol) and paraformaldehyde (21 mg, 0.71 mmol) in THF (3 mL) MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 346 mg, 0.88 mmol) was added and the reaction mixture was agitated at room temperature for 96 hours. Then, the reaction mixture was filtered and concentrated in vacuo to afford (S)-3-[methyl-(1-methyl-piperidin-4-yl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 99%) as an orange oil. The residue was used without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][NH:4][C:5](=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([CH3:22])[C:14]([C:19](Cl)=O)=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OCC)C>[CH3:2][N:3]1[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:22])=[N:12][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:4]1
Reactant: CNNC(=N)c1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCOCC
Product: Cc1ccccc1-c1nc(-c2ccccc2)nn1C
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of 0.56 g. of benzimidic acid 2-methylhydrazide hydrochloride and 3.8 g. of o-toluic acid chloride is heated under stirring at about 120° C. After cooling and addition of diethyl ether, the hydrochloride of the triazole is collected on filter and then suspended in a sodium bicarbonate aqueous solution. The free base is extracted with diethyl ether and the organic phase, after drying over sodium sulfate, is evaporated. The crude compound is purified by distillation at 160° C./0.1 mm Hg. Yield 76%.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:7])=[CH:4][CH2:5]Br.[CH2:8]([OH:12])[CH:9]([CH3:11])[CH3:10]>>[Br:1][CH2:2][C:3]([CH3:7])=[CH:4][CH2:5][O:12][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(=CCBr)CBr
Reactant: CC(C)CO
Product: CC(=CCOCC(C)C)CBr
Reaction time: 2 h

Procedure:
6.8 g (0.03 mol) of 1,4-dibromo-2-methyl-2-butene are dissolved in 15 cc of isobutanol and 2.9 g (0.03 mol) of sodium isobutylate in 50 cc of isobutanol are added at 0°. After stirring at 0° for 2 hours the mixture is stirred at 20°-25° for 16 hours. The mixture is filtered and the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, washed with saturated salt solution and dried with sodium sulphate. The ether is evaporated and the residue is distilled at 13 mm. The product has a B.P. of 128°-138°/13 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
To a solution of 4-benzyloxy-3-hydroxybenzaldehyde(0.5 g) in acetone (12.5 ml) was added milled potassium carbonate (1.20 g) and ethyl bromoacetate (0.48 ml), with stirring. The reaction mixture was heated under reflux for ˜1 hr, with stirring, poured into ice/water and extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel), eluting with dichloromethane, followed by 1% methanol:dichloromethane). The appropriate fractions were collected and combined to give 0.63 g (98%) of product, mp 36-43° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:20])=[O:10])(=[O:5])=[O:4]
Reactant: O=C(O)c1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
A solution of the product of Example 6A (198 mg, 0.8 mmol) in dichloromethane (10 mL) was stirred with oxalyl dichloride (Aldrich, 2.0 mmol) and 1 drop of dimethylformamide at ambient temperature for 2 hours. The title compound was obtained by removing the solvent under vacuum as a yellow oil (250 mg) and the compound was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[Li].CO.C1COCC1>O>[CH3:1][C:2]1[CH:23]=[C:22]([N:24]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[N:25]2)[CH:21]=[CH:20][C:3]=1[O:4][CH:5]([C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of ethyl 4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoate (90 mg, 0.2 mmol), lithium hdroxide monohydrate (24 mg, 1.0 mmol), methanol (2 ml), THF (3 ml), and water (1 ml) was stirred at +45° for 18 hours. The mixture was concentrated, diluted with 8 ml of water and 2 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate-heptane (1:1), extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the target product as a white solid (84 mg, 99%). MS (M+1): 419.2.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].C(N([CH2:16][CH3:17])CC)C.[CH3:18]N(C)C=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.[Cu]I>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:18]#[C:16][CH3:17])[C:3]=1[CH:4]=[O:5]
Reactant: CCN(CC)CC
Reactant: O=Cc1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC#Cc1cccc(F)c1C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 2-bromo-6-fluorobenzaldehyde [see Tetrahedron Letters (1992), 33(49), 7499-7502] (4.0 g; 19.7 mmol) and triethylamine (4.12 ml; 29.5 mmol) in anhydrous N,N-dimethylformamide (75 ml) contained within a large (200 ml capacity) sealed tube was cooled to −78° C. and propyne gas bubbled through until the volume had increased by approx 10 ml. To this mixture was added Pd(PPh3)2Cl2 (0.69 g; 0.99 mmol) and CuI (180 mg; 1.97 mmol), the lid was put in place and the tube allowed to reach room temperature and stir for 4 hours after which TLC showed the reaction was complete. The mixture was poured onto water (500 ml) and extracted with EtOAc (3×150 ml). The combined EtOAc layers were washed with water (3×400 ml), saturated NaCl (150 ml), dried over Na2SO4, filtered through a 1 inch plug of silica and evaporated to give the title compound (3.2 g, 100%).