Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[C:17](=[O:18])[N:7]2[C@@H](C3C=CC=CC=3)[O:9][CH2:10][C@@H:6]2[CH2:5]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[OH:9][CH2:10][C@H:6]1[NH:7][C:17](=[O:18])[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1
Reactant: CC(C)[C@@H]1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H]1C[C@@H](CO)NC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 16.5 g of (3R,6S,7aS)-6-isopropyl-3-phenyltetrahydro-pyrrolo[1,2-c]oxazol-5-one in 175 mL of dichloromethane is treated with 15.35 g of trifluoroacetic acid at room temperature. The resulting solution is stirred for 24 hours at room temperature and a further 14 g of trifluoroacetic acid added. Stirring is continued for a further 24 hours and the solvent removed in vacuum. The residue is treated with 50 mL of water and 100 mL of dichloromethane and the pH of the two-phase mixture adjusted to 12 with concentrated sodium hydroxide solution. Solid sodium chloride is added and the mixture stirred. The organic layer is removed under reduced pressure to give (3S,5S)-5-hydroxymethyl-3-isopropyl-pyrrolidin-2-one as a semi-solid. mp. 55.9° C., [α]D=+47.9° (1% in MeOH)
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[Br:19])=[O:7])C>O>[Br:19][C:9]1[S:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)sc1Br
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Potassium hydroxide (0.65 g, 11.6 mmol) in water (2 mL) was added to a solution of 2-bromo-5-phenyl-thiophene-3-carboxylic acid ethyl ester (3.9 mmol) in IMS (6 mL). The reaction was stirred for 1 hour and then partitioned between diethyl ether and water. The aqueous layer was acidified to pH 7 with 1 N hydrochloric acid and further extracted with diethyl ether. The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated to give the title compound (0.96 g, 87%). LCMS m/z 281.97 [M−H]− R.T.=3.64 min. (Analytical Method 5).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example AX from 4-bromophenyl methyl sulfone and N-Boc-piperazine (31%, white solid, MS (m/e): 241.2(M-Boc, 100%)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])(C)(C)C.Br[C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu](I)I.CCOC(C)=O.C(Cl)Cl>[N:21]1[CH:20]=[C:19]([O:16][C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH:24]=[N:23][CH:22]=1
Reactant: Brc1cncnc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H](N)c1cccc(Oc2cncnc2)c1
Temperature: 115 °C
Yield: 89.6 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 4.2 mmol), 5-bromo-pyrimidine (0.8 g, 5.1 mmol), potassium carbonate (powder, 1.4 g, 10.1 mmol), copper iodide (325 mesh powder, 0.6 g, 3.2 mmol) and pyridine (5 mL) was heated at 115° C. for 24 h. CH2Cl2 (100 mL) was added, the reaction mixture was filtered through celite, rinsed with CH2Cl2 (2×50 mL), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title product (0.81 g, 61% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:31]2[C:14]3[S:15][C:16]([C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:13]=3[CH:12]=[C:11]([O:32][CH3:33])[C:10]=2[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[OH-].[K+].[H-].NN.ClCCl>O(CCO)CCO>[CH2:18]([C:16]1[S:15][C:14]2[C:31]3[C:3]([O:2][CH3:1])=[CH:4][C:5]4[CH:9]=[CH:8][S:7][C:6]=4[C:10]=3[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[CH:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC(=O)c1cc2cc(OC)c3c4sccc4cc(OC)c3c2s1
Agent: NN
Agent: [H-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: ClCCl
Product: CCCCCCCCCCCCc1cc2cc(OC)c3c4sccc4cc(OC)c3c2s1
Temperature: 25 °C

Procedure:
1-(4,9-Dimethoxynaphtho[1,2-b:5,6-b′]dithiophen-2-yl)dodecan-1-one (0.70 g, 1.45 mmol), KOH (1.80 g, 32 mmol), and hydrazine monohydride (1.8 mL, 38 mmol) were heated in 2,2′-oxydiethanol (15 mL) at 200° C. under nitrogen overnight. After the mixture was cooled to room temperature, dichloromethane (100 mL) was added and washed with water (4×50 mL). Dried with Na2SO4, and after solvent was removed, 2-dodecyl-4,9-dimethoxynaphtho[1,2-b:5,6-b′]dithiophene was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[C:8]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)=[C:9]([S:13][CH3:14])[O:10]2)=[CH:5][CH:4]=1.C(=S)=S.[H-].[Na+]>CN(C=O)C.O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:25])[C:8]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[C:9]([S:13][CH3:14])[O:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2c(SC)oc3cc(OC)ccc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: S=C=S
Product: CSc1oc2cc(O)ccc2c(=O)c1-c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Synthesis: Step 1: Synthesis of methyl 4-(7-methoxy-2-(methylthio)-4-oxo-4H-chromen-3-yl)benzoate. A stirred mixture of Intermediate B (100 mg, 0.33 mmol) and carbon disulfide (127 mg, 1.67 mmol) in DMF (5.0 mL) was cooled to 0° C. and NaH (24 mg, 1.0 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 min. Then Mel (94 mg, 0.67 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The solution was diluted with water (10 mL), extracted with DCM (50 mL×3). The organic layers were dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=3:1) to afford product (36 mg (not pure), 30%). MS (ESI): m/z 357.0 [M+1]+.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:32](=[O:33])[N:23]3[CH:24]([C:29](=O)[NH2:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:32](=[O:33])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C(N)=O
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-carbamylpenam (11.01g., 0.024 mole), dry pyridine (4.9g., 0.062 mole) and dry chloroform (250 ml.) is stirred for five minutes and the resulting solution cooled to 0° C. in a wet ice/acetone bath. Phosgene (8.8 ml. of 3.41 molar solution in chloroform) is added by means of a syringe. The reaction mixture is stirred at 5° C. for ten minutes after which the cooling bath is removed and the reaction mixture allowed to warm to room temperature. It is stirred for 30 minutes and then washed successively with water (300 ml.), 1N hydrochloric acid (300 ml.), and water (300 ml.). The chloroform solution is dried (MgSO4), treated with activated charcoal, and filtered through diatomaceous earth. The filtrate is concentrated to reduced pressure and the residue taken up in methylene chloride (450 ml.). The methylene chloride solution is washed successively with 1N hydrochloric acid (150 ml.) and water (300 ml.) and then dried using anhydrous sodium sulfate. The dried solution is then filtered and concentrated under reduced pressure to give the product as a golden foam (7.1 g., 67.3%).
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:13][C:12]2[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=2[NH:10]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Br>CCOC(C)=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][N:10]1[C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[CH2:13][CH2:14][CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:9]1=[O:8]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Yield: 137.3 %

Procedure:
72 mg of sodium hydride in suspension at 60% in oil (1.81 mmol) are introduced, at AT, into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 0.5 g of 2 (1.81 mmol). The medium is stirred for 1 h and then 0.75 g (3.62 mmol) of 3,5-difluorobenzyl bromide is added. The medium is left stirring at AT overnight. 50 ml of EtOAc are added and the organic phase is washed with 50 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 1 g of a white solid is obtained. After trituration with 20 ml of isopropyl ether and filter-drying, 0.62 g of product 3 (white solid) is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:17][C:14]1[C:13]([NH:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:16][N:15]=1
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Reactant: CN(C)S(=O)(=O)Nc1cc(-c2cnc3ccc(Br)cn23)cnc1Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1cc(-c2cnc3ccc(-c4ccnc(C(F)(F)F)c4)cn23)cnc1Cl
Temperature: 100 °C
Yield: 27 %

Procedure:
To a 5 mL microwave tube was added N-(5-(6-bromoimidazo[1,2-a]pyridin-3-yl)-2-chloropyridin-3-yl)dimethylaminosulfonamide (0.080 g, 0.186 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (0.061 g, 0.223 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.014 g, 0.019 mmol), sodium carbonate (0.232 mL, 0.464 mmol), and dioxane (2 mL). The resulting mixture was sealed and underwent microwave heating at 100° C. for 20 min. The solvent was removed. The residue was partitioned between pH 7-buffer (1M TRIS-HCL) and DCM. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, 40 g SiO2, DCM:MeOH (2M NH3)=90%:10% Flow=40 mL/min) to afford the desired product as light yellow solid (25.0 mg). MS (ESI pos. ion) m/z: 496.8. Calcd exact mass for C20H16ClF3N6O2S: 496.1. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.92 (s, 6H) 6.93 (br. s., 1H) 7.78 (d, J=4.82 Hz, 1H) 7.91 (d, J=8.77 Hz, 1H) 7.96 (s, 1H) 8.07 (s, 1H) 8.22 (s, 1H) 8.33-8.44 (m, 2H) 8.70 (s, 1H) 8.90 (d, J=5.26 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[O-]C#[N:14].[K+].Cl[O-].[Na+].Cl[O-]>O>[NH2:14][CH2:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: N#C[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NCS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of methanesulfonyl-piperazine are dissolved in 50 ml of water; after adding 6.2 ml of concentrated hydrochloric acid thereto, a solution of 5.4 g of potassium cyanate in 20 ml of water is added dropwise, and the thus-obtained mixture is stirred for 4 hours at room temperature. The precipitate which separates out is filtered off and dried. Yield: 11 g; melting point: 254° C. 10 g of the dried precipitate and 4 g of sodium hydroxide solution in 80 ml of water are cooled to 0° C., and 0.052 mol of sodium hypochlorite, which has been pre-cooled to 0° C., is added. The mixture is then stirred at room temperature until no further hypochlorite is detectable. The aqueous solution of 1-aminomethanesulfonylpiperazine, which is obtained in this way, is directly useful in the further reaction.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:30])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13](C2C=CC(C(OC(C)(C)C)=O)=CC=2N)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](O)([C:33](F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:30])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:33]2[CH:31]=[CH:5][C:1]([NH2:6])=[CH:2][CH:3]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)c(N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
Cyclopentyl-[2-(4-BOC-aminophenyl)-5-chloro-1H-indol-7-yl]-amine (430 mg, 1 mmol) prepared in Example 78 was added to DCM (5 mL). TFA (5 mL) was added thereto, and the mixture was stirred for 2 h. After completion of the reaction, TFA was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (310 mg, Yield 95%).
Reaction SMILES: [CH:1](Br)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(C)=[O:20].C([O-])(O)=O.[Na+]>>[CH:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC=CBr
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC/C=C\CCCCCCCCCC=O
Temperature: 60 °C
Yield: 38 %

Procedure:
Run 3 (invention): The oxidation procedure employed for run 2 was repeated on a larger scale. Thus, 360 g (1.2 mol) of hexadecenyl bromide and 1800 mL (1980 g; 25.4 mol) of DMSO were mixed and heated to 60° C., with temperature maintained at 60° C. for about 30 minutes. Then, 240 g (2.9 mol) of NaHCO3 was added and the temperature of the reaction mixture raised to 130° C., which was maintained for 2 hours. The reaction mixture was then cooled and filtered. The lower layer (DMSO layer) was separated and extracted with about 1 L of hexane. The hexane extract and upper (aldehyde) layer were combined, washed once with about 100 mL of water, then concentrated on a rotary evaporator. GLC analysis indicated an aldehyde/alcohol ratio of 4.5:1. A distilled yield of 38% Z-11-hexadecenal was obtained.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: NC1CCc2ccc([N+](=O)[O-])cc21
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 6-nitro-1-aminoindane hydrochloride (1.90 g, 8.85 mmol) in DMF (30 ml) was added triethylamine (250 ml, 18.06 mmol) followed by benzyl bromide (1.07 ml, 9.03 mmol). The mixture was warmed to room temperature, stirred for 3 hr, dumped into water (100 ml), and extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered through a small plug of silica gel and reduced to a syrup. The titled compound was isolated as the hydrochloride salt: (1.34 g, 50%); m.p. 234°-235° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16](=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][CH3:40])[CH2:34]4)=[O:32])=[CH:27][N:26]=3)[CH:18]=2)[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16](=[O:41])[C:17]2[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][CH3:40])[CH2:34]4)=[O:32])=[CH:27][N+:26]=3[O-:9])[CH:18]=2)[CH2:14][CH2:13]1
Reactant: CCC1CCCN(C(=O)c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)nc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC1CCCN(C(=O)c2ccc(-c3cc(C(=O)NC4CC4)cc(F)c3C)[n+]([O-])c2)C1
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of N-cyclopropyl-3-{5-[(3-ethylpiperidin-1-yl)carbonyl]pyridin-2-yl}-5-fluoro-4-methylbenzamide (Intermediate 33, 10.5 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give N-cyclopropyl-3-{5-[(3-ethyl-1-piperidinyl)carbonyl]-1-oxido-2-pyridinyl}-5-fluoro-4-methylbenzamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[F:34][C:35]1[CH:58]=[CH:57][C:38]([CH2:39][N:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[N:42]=[C:41]2[C:49]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[O:50])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:54]2[CH2:55][CH2:56][CH:51]([C:49]([C:41]3[N:40]([CH2:39][C:38]4[CH:37]=[CH:36][C:35]([F:34])=[CH:58][CH:57]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)=[O:50])[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.26 g, 0.488 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.25 g, 0.73 mmol), and potassium carbonate (0.20 g, 1.46 mmol) in toluene/water (10/1)(5 mL). Heat to reflux. After 3 days, cool and evaporate in vacuo to obtain a residue. Partition the residue between dichloromethane and water. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10/1 ethyl acetate/methanol to give the title compound: Rf=0.28 (silica gel, 10/1 ethyl acetate/methanol).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(Br)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Yield: 99 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (4.3 g) and cyclopentylacetyl chloride (3.46 g) were mixed in acetonitrile (50 mL) and tetrahydrofuran (20 mL) and the reaction mixture was heated to reflux for 1 hour. Potassium carbonate (4.5 g) was added and the reaction mixture was refluxed for 1 hour and then poured onto crushed ice and saturated aqueous potassium carbonate (50 mL). The product was collected by filtration and washed with water (100 mL) to furnish 6.6 g (100% yield) of the title compound as a solid. LC-MS (m/z) 311 (MH+); tR=3.07, (UV, ELSD) 100%, 100%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 6H), 2.25 (m, 1H), 2.31 (d, 2H), 7.27 (s, 2H), 9.23 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2].CS(C)=O.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:29][CH2:28][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][C:10]=3[Br:17])[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cccc(Br)c3nc21
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCC3CCCCC3)c3cccc(Br)c3nc21
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-8-bromo-1H-pyrazolo[3,4-b]quinoline (2.0 g, 6.44 mmol), DMSO (5 ml) and cyclohexylmethylamine (1.46 g, 12.9 mmol) is heated at 80°-90° C. for 3 hours. The reaction mixture is cooled to room temperature and then is poured into water. The resulting solid is collected by filtration, washed with water and evaporated. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 2.0 g (80%) of 1-ethyl-8-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 160°-162° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[N:11]([CH2:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[CH:10]=1)=[O:8]
Reactant: O=C(Nc1nccs1)c1c[nH]c2cc(F)ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccn2)cc1
Product: O=C(Nc1nccs1)c1cn(CCc2ccccn2)c2cc(F)ccc12

Procedure:
The title compound was prepared using 6-Fluoro-1H-indole-3-carboxylic acid thiazol-2-ylamide and toluene-4-sulfonic acid 2-pyridin-2-yl-ethyl ester as R5X.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])([O:12][CH2:13][CH3:14])=[O:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccccc1N
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1N=C(C)c1ccccc1

Procedure:
A solution of acetophenone (100 ml), o-carbethoxyaniline (90 ml), benzene (100 ml) was refluxed in the presence of molecular sieve (40 g) with continuous removal of water. N-(α-methyl benzylidene)-o-carbethoxyaniline (XV) was obtained by fractional distillation. XV had a boiling point of 123° at 0.1 millimeter.