Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([F:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Cl)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Triethylamine (“TEA”) (0.741 mL, 5.31 mmol; d. 0.726) was added to a cold (0° C.) solution of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (1.08 g, 3.54 mmol) in DCM (10 mL), followed by addition of methanesulfonyl chloride (0.329 mL, 4.25 mmol). After 1 hour, the reaction mixture was diluted with DCM, and the organic layer was washed with saturated aqueous NaHCO3, dried, filtered and concentrated to afford 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (1.30 g, 3.39 mmol, 95.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74 (d, 1H), 5.32 (d, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:22]([O:24][C:25](=[O:31])[CH2:26][CH:27]([CH3:30])[CH2:28]Br)[CH3:23]>CN(C=O)C>[CH3:28][CH:27]([CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)[CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:31]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CCOC(=O)CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.02 g) in dry DMF (10 ml) was added sodium hydride (60% dispersion in mineral oil, 0.16 g) and the mixture stirred for 1 hour at room temperature. To the resulting solution was added ethyl-4-bromo-3-methylbutyrate and the mixture stirred for 16 hours. Solvent was evaporated and the residue partitioned between water and dichloromethane. Insoluble material was removed by centrifugation. The organic layer was filtered through phase separating paper (Whatman IPS) and the residue was purified by flash chromatography on silica gel by elution with methanol/dichloromethane/concentrated ammonia (50/950/5) to give ethyl 3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (0.27 g) which was hydrolysed in methanol (3 ml) and aqueous sodium hydroxide (1N, 2 ml) for 2 hours at room temperature. The solution was evaporated and the residue purified by reverse phase h.p.l.c (water/acetonitrile/0.1% TFA gradient) to give a glass which crystallised on trituration with ether to give the title compound (0.08 g): m.p. 169°-171° C.; NMR(d6DMSO) δ13.45(1H,broad), 12.07(1H,broad) 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m), 2.37(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+ ; calculated for C22H25N3O4F3. 0.5 H2O: C, 55.2; H, 5.6; N, 8.9. Found: C, 55.3; H, 5.6; N, 8.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].Cl>CC(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)Cl)c2)C1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)NCC(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoyl chloride (2.4 g.) and glycine (525 mg.) are dissolved in 30 ml. of water, 30 ml. of acetone and 14 ml. of 1 N sodium hydroxide. After stirring at room temperature for about 25 minutes, the reaction mixture is acidified with concentrated hydrochloric acid. The precipitated material is recrystallized from acetone (25 ml.)-hexane (40 ml.) to yield the product, m.p. 189.5°-191.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.[NH4+].[Cl-].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH2:35])=[O:22])[CH2:17][CH2:18]3)[CH:12]=2)=[CH:4][C:3]=1[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: Nc1ncc(-c2cnn(C3CCN(CC(=O)O)CC3)c2)cc1-c1nc2ccccc2s1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of {4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidin-1-yl}-acetic acid (10.0 mg, 0.0184 mmol), NH4Cl (2.0 mg, 0.037 mmol), TBTU (8.86 mg, 0.0276 mmol) and DMF (1 mL) was charged with DIPEA (0.03 mL, 0.2 mmol) and allowed to stir at rt for 10 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.17-2.35 (m, 4H), 2.69 (td, J=11.9, 2.5 Hz, 2H), 3.28 (d, J=12.4 Hz, 2H), 3.37 (s, 2H), 4.29-4.40 (m, 1H), 7.41-7.47 (m, 1H), 7.53 (td, J=7.6, 1.3 Hz, 1H), 7.89 (s, 1H), 8.01 (dd, J=12.3, 8.0 Hz, 2H), 8.11 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.3 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[C:14]=2[N:22]=1)[CH3:8]>ClCCl.C(Cl)(Cl)Cl>[CH2:7]([O:9][CH2:10][C:11]1[N:12]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:29][CH2:30]2)[C:13]2[C:18]([CH3:19])=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[C:14]=2[N:22]=1)[CH3:8]
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCC1CCN(C(=O)C(C)C)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
Isobutyryl chloride (96 μL, 0.917 mmol) was added drop wise to a chilled (0° C.) solution of 2-(ethoxymethyl)-6,7-dimethyl-1-(2-piperidin-4-ylethyl)-1H-imidazo[4,5-c]pyridin-4-amine (304 mg, 0.917 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to stir overnight then it was diluted with chloroform and washed with 5% sodium hydroxide, water and brine. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 185 mg of 2-(ethoxymethyl)-1-[2-(1-isobutyrylpiperidin-4-yl)ethyl]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine as a yellowish solid, m.p. 167.5-169.2° C.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[ClH:22].[CH2:2]([NH:9][C:17](=[O:19])[CH2:16][O:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)COC1CCN(Cc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
2-(1-Benzylpiperidin-4-oxy)acetic acid, hydrochloride, (7.0 g) and thionyl chloride (5 ml) in dry chloroform (100 ml) were heated under reflux for 21/2 hours. The solvent was evaporated in vacuo and the resulting acid chloride taken up in chloroform (50 ml) and added dropwise to a solution of n-butylamine (5 ml) in chloroform (50 ml) with stirring at 0°. The solution was stirred at 0° for 4 hours then left at room temperature overnight. The chloroform solution was washed with water (3×50 ml), sodium hydroxide solution (3×50 ml, 2 N) and hydrochloric acid solution (3×50 ml, 2 N). The aqueous acid solution was basified to pH 12 and extracted with chloroform (3×100 ml). The chloroform extract was dried and the solvent evaporated in vacuo. The residue in ether was treated with ethereal hydrogen chloride, the resulting solid collected, washed with ether and dried to give N-n-butyl-2-(1-benzylpiperidin-4-oxy)acetamide, hydrochloride (3.5 g) identified by n.m.r. spectroscopy.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:23]([O:25]CC)=[O:24])([CH3:22])[CH3:21])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)C.[OH-].[K+].Cl>C(O)C.O>[C:23]([C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)([OH:25])=[O:24]
Reactant: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC1(CCCCC(C)(C)C(=O)O)SCCCS1)C(=O)O
Yield: 95.5 %

Procedure:
A solution of 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (870 mg, 1.89 mmol) and potassium hydroxide (85%, 750 mg, 11.33 mmol) in ethanol (16 mL) and water (4 mL) was heated under reflux for 3 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 4 with 1 N HCl (8 mL). The emulsion was extracted with dichloromethane (3 75 mL). The combined organic phases were washed with water (50 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid (730 mg, 95%) as a viscous, yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): (ppm): 2.80 (m, 4H), 1.94 (m, 2H), 1.85 (m, 4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm): 185.08, 53.36, 42.28, 40.52, 38.27, 26.18, 25.69, 25.23, 25.11, 24.73. HRMS (LSIMS, nba): Calcd. for C20H37O4S2 (MH+): 405.2133, found: 405.2115.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>C(Cl)Cl>[C:12]([O:11][C:9]([NH:8][C@@H:3]([CH2:2][NH:1][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[C:4]([O:6][CH3:7])=[O:5])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of methyl 3-amino-2(S)-(tert-butoxycarbonylamino)propanoate ii (1.6 g, 7.3 mmoL) in DCM (50 mL) was added DIPEA (1.64 mL, 9.4 mmoL) and 2-nitrobenzene sulfonyl chloride (1.62 g, 7.3 mmoL). The mixture was stirred at rt for 2 h. It was then concentrated, dissolved in ethyl acetate, which was then washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. It was then filtered, concentrated to yield 2.9 g (98%) of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitrophenylsulfonamido)propanoate iii as a yellow foam. 1H NMR (CD3OD, 300 MHz) δ 1.41 (s, 9 H), 3.36-3.51 (m, 2 H), 3.71 (s, 3 H), 4.22 (m, 1 H), 7.80-7.90 (m, 3 H), 8.07-8.10 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][N:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cn1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC)cn1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(5-methoxypyridin-2-yl)indole-3-carboxylic acid ethyl ester (139 mg, 0.35 mmol, see step (b) Example 13) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 110 mg (58%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Na+].[Cl-]>CN1CCCC1=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 120 °C
Yield: 92.3 %

Procedure:
A homogeneous mixture of 4-fluoro-3-methylnitrobenzene 1 (20 g, 129 mmol) and N-methylpiperazine 3 (25.82 g, 258 mmol) in N-methylpyrrolidone (NMP) (10 mL) was refluxed (120° C.) under N2 for 24 hours. The reaction mixture upon cooling to room temperature was poured over a saturated NaCl solution (100 mL). The resulting solid was sonicated for approx. 30 seconds, filtered, washed with ice-cold water (2×10 mL) and dried under high vacuum to obtain 4-(4-methylpiperazinyl)-3-methylnitrobenzene 5 (28 g, 92%). 1H NMR (CD3OD): δ 8.02 (m, 2H), 7.13 (d, 1H, J=9.3 Hz), 3.08 (m, 4H), 2.66 (m, 4H), 2.38 (s, 6H); LCMS: purity: 99%, MS (m/e): 236 (MH+).
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:16])[N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].C([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:32])=[O:33])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:16])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(C)n3S(=O)(=O)c2ccccc2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C)cc3c2)c1F

Procedure:
2,6-Difluoro-N-(2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.379 g, 0.691 mmol) was dissolved in MeOH (6 mL) and water (2 mL). K2CO3 (1.91 g, 13.8 mmol) was added, and the reaction mixture was stirred at reflux overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to a solid. The solid was triturated with DCM to provide 2,6-difluoro-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a solid (150 mg, 53% for three steps). 1H NMR (400 MHz, DMSO-d6) δ 11.48 (br s, 1H), 10.80 (s, 1H), 9.80 (br s, 1H), 8.26 (br s, 1H), 8.20 (br s, 1H), 7.53-7.59 (m, 1H), 7.25-7.30 (m, 1H), 6.17 (br s, 1H), 3.10-3.14 (m, 2H), 2.40 (br s, 3H), 1.74-1.82 (m, 2H), 0.98-1.03 (m, 3H); m/z (APCI-neg) M−1=407.2.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:6][C:5]([CH3:20])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C1(C)C(C)=CC=CC=1>N1C=CC=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[S:22][C:2]2=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A mixture of N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide (5.0 g, 17.1 mmol) and P2S5 (7.6 g, 34.2 mmol) in pyridine (50 mL) and p -xylene (200 mL) was stirred at 140° C. for 20 h. The hot solution was transferred to another flask and the solvent was removed in vacuo. The residue was purified by recrystallization from EtOH to afford 6-methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a yellow solid (3.5 g, yield: 75%).
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]([O:28][CH3:29])/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].P(O)(O)([O-])=O.[Na+]>O1CCCC1.CCCCCC>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([C:6]([CH3:7])([CH3:8])[CH:22]([CH:21]([O:28][CH3:29])[O:20][CH3:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)/C=C/C(OC)OC
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
3.4 ml of a 1.95 M of butyllithium per liter of hexane were added at -70° C. to a mixture of 1.24 g of p-tolyl isopropyl sulfone in 13 ml of tetrahydrofuran and after stirring the mixture for 15 minutes, a solution of 1 g of methyl (E) 4,4-dimethoxy-2-butenoate in 20 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred at -20° C. for one hour and was then poured into an aqueous monosodium phosphate solution. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an ether-petroleum ether (b.p. =40° to 70° C.) mixture to obain 1.1 g of methyl 4-p-tolylsulfonyl-4-methyl-3-dimethoxymethyl-pentanoate melting at 110° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.56 ml) and octadecyl isocyanate (1.26 ml) were added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (1.05 g) in methylene chloride (11 ml) and stirred for 3 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol=60:1 to 50:1), thereby yielding the entitled compound (1.78 g) as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)[C:3]1=[O:38]>C(O)(C(F)(F)F)=O.ClCCl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:4]2[C:3](=[O:38])[N:2]([CH3:1])[CH:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[CH:5]=2)[CH2:25]1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)c(=O)n(C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(N3CCC[C@H](N)C3)c(=O)n(C)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-oxo-3-pyridyl]-3-piperidyl]carbamate (0.2245 mmol; 116.0 mg) in TFA (1 mL) and dichloromethane (4 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 233 as an off-white solid (51.6 mg, 54%). 1H NMR (400 MHz, DMSO) δ 9.47-9.40 (s, 1H), 9.36-9.30 (s, 1H), 8.66-8.57 (s, 2H), 8.48-8.40 (s, 1H), 7.96-7.90 (d, J=2.5 Hz, 1H), 6.96-6.90 (d, J=2.5 Hz, 1H), 3.69-3.61 (d, J=6.6 Hz, 2H), 3.58-3.52 (s, 3H), 2.83-2.72 (t, J=9.7 Hz, 1H), 2.63-2.58 (s, 3H), 2.30-2.23 (m, 1H), 1.88-1.81 (d, J=9.0 Hz, 1H), 1.74-1.68 (d, J=13.3 Hz, 1H), 1.63-1.53 (d, J=12.8 Hz, 1H), 1.18-1.06 (m, 1H); MS (ESI) m/z: 417.2 [M+H]+
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].CC#N.[Cl:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:11]([O:19][CH2:2][O:3][CH3:4])[CH:10]=1
Reactant: COCCl
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COCOc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Neat chloro(methoxy)methane (1.8 mL, 23.8 mmol) was added to a MeCN solution (20 mL) of 3-chloro-5-(trifluoromethyl)phenol (3.6 g, 18.3 mmol) and Cs2CO3 and the resulting mixture was stirred at room temperature. After 5 h the resulting mixture was diluted with diethyl ether, filtered and concentrated. The resulting material was filtered through a short pad of silica gel, followed by concentration to yield 1-chloro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:28]([C:27]4[CH:31]=[CH:32][N:33]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:26]=4)=[O:29])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: CN(C)c1cc(C(=O)O)ccn1
Agent: Cl
Product: CN(C)c1cc(C(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccn1

Procedure:
Prepared as in Example 2 from (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a) and 2-(dimethylamino)isonicotinic acid (8%). 1H NMR (400 MHz, DMSO-d6, 60° C.) δ 1.45 (br m, 2H), 1.68 (br m, 1H), 1.90 (br m, 1H), 2.16 (br m, 2H), 3.00 (s, 6H), 3.30-4.09 (br m, 4H), 6.44 (d, J=5.6 Hz, 1H), 6.47 (s, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.69 (d, J=6.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.67 (br s, 2H), 10.67 (br s, 1H). MS 459 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Br.[CH3:16][C:17]1([CH3:24])[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1>>[CH3:16][C:17]1([CH3:24])[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CC1(C)CCN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Br
Product: CC1(C)CCn2c(nc(-c3ccncn3)cc2=O)N1

Procedure:
A mixture of 2.39 g (12.31 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582), 2.33 g (11.19 mmol) 6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide