Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:4]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:25]/[C:24]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:26])=[C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:4]=1
Reactant: COc1cc(OCc2ccccn2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OCc2ccccn2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 90 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-114A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 90% yield, mp 188–189° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.66 (d, 1H, J=3.6 Hz), 8.28 (s, 1H), 8.21 (d, 2H, J=7.8 Hz), 8.11 (d, 1H, J=15.4 Hz), 7.89–7.99 (m, 4H), 7.57–7.68 (m, 4H), 7.53 (dd, 1H, J=5.4, 1.5 Hz), 7.41–7.45 (m, 1H), 7.13 (dd, 1H, J=5.4, 3.6 Hz), 7.02 (s, 1H), 5.45 (s, 2H), 3.99 (s, 3H). MS (ESI) m/z=507 ([M+H]+, 100%). Anal. Calcd. for C26H22N2O5S2.½H2O: C, 60.57; H, 4.50; N, 5.43; S, 12.44. Found: C, 60.92; H, 4.54; N, 5.48; S, 12.32.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH:33]([CH3:35])[CH3:34]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH:33]([CH3:35])[CH3:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)C)CC1
Yield: 13 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13), sodium hydride and 2-bromopropane, to give the desired product as a light brown foam (13%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C(O)C.[CH:21](Br)([CH3:23])[CH3:22]>[OH-].[K+]>[CH:21]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])([CH3:23])[CH3:22]
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Reactant: CC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1cccc(OC(C)C)c1
Reaction time: 1 h

Procedure:
A 22.7 g (0.1 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in 100 ml of 1N-potassium hydroxide solution. To this solution 150 ml of ethanol was added and the mixture was stirred for one hour, which was followed by the addition of 12.3 g (0.1 mol) of isopropylbromide. After the addition of the iso-propylbromide, the reaction mixture was warmed and stirred under reflux for 4 hours. After distillation of most of the ethanol, the oily material remaining was extracted with benzene and the residue was distilled to obtain 20.9 g (77.9%) of a red, viscous oil having a boiling point of 186°C/0.08 mm Hg. The product was recrystallized from a mixture of benzene and n-hexane (1:1 ) as white prismatic crystals having a melting point of 92°C. IR cm-1 (KBr-tablet) νNH 3250(S), νCH 2980(S), νCO 1660(S), 1610(S).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.[F:19][CH2:20][CH2:21]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:21][CH2:20][F:19])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CCF
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (400 mg, 1.311 mmol), 1-fluoro-2-iodoethane (684 mg, 3.93 mmol) and potassium carbonate (544 mg, 3.93 mmol) in DMF (4 ml) was heated under stirring for 3 h. The reaction mixture was cooled down and diluted with water (20 ml), the resulted mixture was extracted with DCM (3×20 ml). The combined organic phase was washed with water, brine, dried over sodium sulfate, concentrated to give the crude material which was purified by column chromatography eluted with ethyl acetate/cyclohexane 0-40% to give product 0.21 g. 1H NMR (500 MHz, CDCl3): 7.39-7.48 (m, 5H), 4.89 (s, 2H), 4.77 (t, 1H), 4.67 (t, 1H), 4.21 (t, 1H), 4.16 (t, 1H), LCMS (Method D): RT=1.24 min, M+H+=353.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (4 g, 28.35 mmol, 1.00 equiv), 4-fluorophenol (3.177 g, 28.34 mmol, 1.00 equiv) and potassium carbonate (7.83 g, 56.24 mmol, 1.98 equiv) in N,N-dimethylformamide (50 mL) was stirred overnight at 120° C. The reaction was cooled to room temperature and then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 6.4 g (97%) of 1-fluoro-4-(4-nitrophenoxy)benzene as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.22-8.18 (m, 2H), 7.16-7.04 (m, 4H), 7.00-6.97 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[CH3:38][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:38])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
A solution of N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.26 mmol) in 1,4-dioxane (3 mL) with PdCl2(dppf) (0.047 g, 0.064 mmol) was degassed for 5 min. To this mixture was added 2.0M dimethylzinc in toluene (0.39 mL, 0.77 mmol). The reaction mixture was heated to 80° C. After 2 h, the reaction was quenched slowly with MeOH (15 mL) and then was further diluted with DCM (50 mL), filtered through a nylon membrane and evaporated to a crude yellow residue. The residue was purified by silica gel chromatography eluting 0-100% EtOAC/hexanes, followed by 10% EtOH/EtOAc. The resulting solid was dissolved in DCM (10 mL) and hexanes (20 mL) added to afford the title compound as a yellow solid (0.02 g; 13.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.51-7.60 (m, 2H), 7.40-7.50 (m, 3H), 7.32-7.39 (m, 1H), 6.07 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.48-3.53 (m, 4H) *Note: The 2-Me group is submerged under the water peak at 2.5 ppm. MS (ESI) 564.1 [M+H]+.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].[O-]CC.[Na+].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH2:23]Cl>C(O)C.[Cl-].[Na+].O>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:23][C:22]1[NH:21][CH:20]=[N:19][C:18]=1[CH3:17])=[N:9][CH2:10][C:11]#[CH:12])#[N:2]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: Cc1nc[nH]c1CCl
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A solution of 0.029 g (0.16 m mole) of the product of step A, in 1 ml ethanol containing 0.42 m mole sodium ethoxide, was placed under a nitrogen atmosphere and cooled to 4° C. with stirring. After 5 minutes, 0.035 g (0.21 m mole) of solid 4-methyl-5-chloromethylimidazole was added. The mixture was stirred for 40 minutes, poured into brine (30 ml) and then extracted with chloroform (3×15 ml). After drying (Na2SO4), the solvent was removed by evaporation. The residue was purified by thin layer chromatography on silica gel plates using a methanol-chloroform (1:4) solvent system to give 0.022 g (50%) of the title compound as a syrup which crystallized on standing at room temperature. Trituration with chloroform gave the crystalline product, m.p. 147°-149° C. I.R. (nujol): 3360 (NH), 3300 (C≡CH), 2160 (C≡N), 1600 and 1585 (C=N) cm-1 ; n.m.r. (acetone D6): δ 8.53 (1H, NH), 7.68 (s, 1H), 7.00 (1H, NH), 4.13 (q, 2H, J=2.5 Hz), 3.73 (s, 2H), 3.53 (m, 2H), 2.73 (m, 3H), 2.21 (s, 3H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10]>ClCCl>[CH3:7][C:8]([CH3:15])([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:4])=[O:10]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C=CCC(C)(C)C(=O)Cl
Reaction time: 3 h

Procedure:
Oxalyl chloride (5.1 mL, 58 mmol) was added to a 0-5° C. solution of 2,2-dimethyl-4-pentenoic acid (5.00 g, 39.0 mmol) in 25 mL of dichloromethane. The mixture was stirred for 3 h, then concentrated to afford crude 2,2-dimethyl-4-pentenoyl chloride, which was dissolved in 10 mL of dichloromethane for use in the next step.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](O)=[O:11]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([Cl:3])=[O:11]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)COc1ccc(Cl)cc1Cl

Procedure:
46 ml of thionyl chloride were added over 30 minutes to a solution of 130 g of 2,4-dichlorophenoxy-acetic acid in 150 ml of benzene, and the mixture was refluxed for one hour. The solvent and the excess thionyl chloride were eliminated under reduced pressure and the residue was distilled under 0.1 mm of mercury to obtain 91.4 g of the sought product with a boiling point of 120° C. at 0.1 mm of mercury.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]Cl.CN(C)C=O>O>[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2ccc(OC/C=C\CCl)cc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 1.7 g of potassium carbonate, 3.2 ml of cis-1,4-dichloro-2-butene and 50 ml of dimethylformamide was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with ethyl acetate and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and 7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one (1.3 g) was obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:37](=[O:40])[CH:38]=[CH2:39])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.7 %

Procedure:
[1-(4-Amino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid benzyl ester (1.29 g, 3.3 mmol) was dissolved in DCM (20 ml). To this was added diisopropylethylamine (1.64 ml, 9.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.3 ml, 3.6 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The THF was removed under vacuum and the resulting crude material was purified by Prep HPLC to give the title compound (10.4 mg, 1% yield) as a white powder.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(O)C.[O-]CC.[Na+].Cl[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7]([C:6]1([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:23][CH:22]1[CH:21]=[CH2:20])=[O:8])[CH3:11]
Reactant: ClC/C=C/CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115 %

Procedure:
35.2 g (220 mmol) of malonic acid diethyl esterdiethyl malonate and 400 mL of toluene were added into a three-necked flask (1 L), and thereafter, 82.3 mL (210 mmol) of a 20% sodium ethoxide ethanol solution was added thereto as a base. The obtained mixture was stirred at room temperature for 0.5 hours, and 12.5 g of trans-1,4-dichloro-2-butene (100 mmol; a reagent manufactured by Tokyo Chemical Industry Co., Ltd.) was then added to the reaction solution. The obtained mixture was stirred at room temperature for 5 days, and 240 mL of a 1 M sodium hydroxide aqueous solution was then added to the reaction solution. The mixture was stirred for 1 hour, and an organic layer was then separated. A water layer was re-extracted with 200 mL of toluene, and organic layers were then gathered. The gathered organic layer was washed with 200 mL of water three times, and the resultant was then filtrated, while washing the residue with toluene. The obtained filtrate was concentrated at 45° C. under reduced pressure, so as to obtain 24.4 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane in the form of a crude product of a light yellow oily substance. This crude product contained 19.5 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane (yield: 92%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:26])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 358.1 [M+H]+.
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].O>C(O)(C)C>[C:1]([S:14]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH3:21])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:11])([F:13])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCN(CC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 56 °C

Procedure:
A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2NH(C4H9) (133.0 g; 0.375 mole), and sodium carbonate (33.0 g). The mixture was heated to 93° C. and ethyl bromoacetate (69.0 g; 0.411 mole) was slowly added over a period of 8 hours, and then the ensuing mixture was allowed to stir overnight at 93° C. To this mixture was added water (120.0 mL) and the temperature was 56° C., at which point sulfuric acid (39.0 g; concentrated) at a rate to keep the temperature below 100° C. Two phases formed and the bottom layer was recovered and washed with water (150 mL). This crude material was distilled (110-125° C.; 3.3 mm Hg) to yield C4F9SO2N(C4H9)CH2CO2C2H5 (107.0 g). A one-liter flask fitted with a thermocouple, addition funnel, heating mantle, reflux condenser and overhead stirrer was charged with C4F9SO2N(C4H9)CH2CO2C2H5 (103.0 g; 0.241 mole) KOH (18.0 g; 0.273 mole) water (50 mL) and isopropanol (50.0 g). The mixture was heated at reflux for 2 hours, and a Dean-Stark trap was added. As isopropanol was removed from the trap, an equivalent amount of water was added to the reaction mixture. When the reaction mixture reached 101° C. water (25 mL) was added and the mixture was cooled to 56° C.; upon addition of sulfuric acid (26.7 g; concentrated) the temperature rose to 78° C. and two phases appeared. The bottom phase was distilled (139-147° C.; 3.6 mm Hg) to yield a crème colored solid, C4F9SO2N(C4H9)CH2CO2H.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.O.[NH3:12]>>[CH3:1][C:2]1([CH3:10])[O:9][CH2:8][C@@H:7]([NH2:12])[C@H:5]([OH:6])[CH2:4][O:3]1
Reactant: N
Reactant: CC1(C)OCC2OC2CO1
Solvent: O
Product: CC1(C)OC[C@@H](N)[C@H](O)CO1
Temperature: -70 °C
Yield: 87 %

Procedure:
A steel bomb was charged with liquid ammonia (60 ml) with cooling in an isopropanol-dry ice bath maintained at -70° C. The epoxide (III) (21.46 g, 0.15 mole) was added to it, followed by water (2.70 ml, 0.15 mole). The bomb was sealed and, then, heated in an oil bath at 120° for 4 hr. The bomb was cooled, opened and the ammonia was allowed to evaporate. The crude residue was triturated with ether, chilled, and the crystalline product was isolated by filtration. The amine (IV) was obtained as white prisms. (18.78 g, yield 87%). m.p. 81.5°-82.5°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20](C)=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.N1([CH2:38][C:39]2[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=2)[NH2:42])CCCC1.Cl>CC(O)C>[NH2:3][CH:4]1[CH2:38][C:39]2[CH:40]=[C:41]([NH:42][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:22]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][C:26]6[S:27][CH:28]=[CH:29][CH:30]=6)[CH:20]=[CH:19][CH:18]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=[CH:44][C:45]=2[CH2:6][CH2:5]1
Reactant: Cc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CC(C)O
Product: NC1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)Cc6cccs6)c5)nn5ccccc45)n3)cc2C1
Yield: 44.5 %

Procedure:
N-{5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-methylphenyl}-2-(2-thienyl)acetamide (100 mg, 0.22 mmol), 3-(1-pyrrolidinylmethyl)aniline (78 mg, 0.44 mmol) and catalytic conc. HCl in iPrOH (4 mL) were heated in a microwave at 180° C. for 10 min. The reaction was concentrated and the residue was dissolved in DCM. The organic solution was washed with saturated NaHCO3 (aq) and water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography. Fractions containing pure product were concentrated, taken up in MeOH and neutralized with MP-carbonate. The mixture was filtered and the filtered concentrated and triturated with DCM and hexanes to give the title compound (28 mg, 21%). 1H NMR (400 MHz, d6-DMSO) δ 9.62 (s, 1H), 9.50 (s, 1H), 8.80 (d, J=6.8 Hz, 1H), 8.50 (d, J=9.2 Hz, 1H), 8.21 (d, J=5.6 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.45-7.41 (m, 1H), 7.36 (m, 1H), 7.32-7.28 (m, 2H), 7.16 (t, J=7.8 Hz, 1H), 7.11-7.07 (m, 1H), 6.98-6.95 (m, 2H), 6.87 (d, J=7.2 Hz, 1H), 6.50 (d, J=5.6 Hz, 1H), 3.91 (s, 2H), 3.50 (s, 2H), 2.39 (m, 4H), 2.26 (s, 3H), 1.65-1.64 (m, 4H) ppm. ES-LC/MS m/z=600 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:25])[CH2:13][CH2:14][C:15]1([C:21](OC)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.Br[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]1[CH2:13][CH2:14][C:15]3([CH2:20][CH2:19][N:18]([CH2:29][CH2:30][O:31][C:32]4[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=4)[CH2:17][CH2:16]3)[C:21](=[O:22])[O:25]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: Fc1cc(F)cc(OCCBr)c1
Reactant: COC(=O)C1(CCC(O)c2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2ncc(Cl)c(C3CCC4(CCN(CCOc5cc(F)cc(F)c5)CC4)C(=O)O3)c2c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 83.6 %

Procedure:
A mixture of 1 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidine-4-carboxylate, 0.8 g of 1-(2-bromoethoxy)-3,5-difluorobenzene and 0.42 g of potassium carbonate in 45 cm3 of acetonitrile was maintained at a temperature of 80° C. with stirring and under an argon atmosphere for 20 hours. The suspension was filtered, the insoluble material was washed with ethyl acetate and the filtrate was then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was purified by chromatography under a pressure of 100 kPa of argon, on a column of silica gel (particle size 40-60μ; diameter 3.5 cm; height: 38 cm), eluting with a dichloromethane/methanol mixture (97/4 by volume) and collecting 35-cm3 fractions. Fractions 9 to 20 were combined and then concentrated to dryness under the above conditions. 1.1 g of 3-(3-chloro-6-methoxyquinolin-4-yl)-9-[2-(3,5-difluorophenoxy)ethyl]-2-oxa-9-azaspiro[5.5]undecan-1-one were obtained.