Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.C1C[O:30]CC1>O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])(=[O:30])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)C2CCCCC2)cc1
Reactant: C1CCOC1
Solvent: O
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-{[4-(2-butynyl oxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide (180 mg, 0.52 mmol) in MeOH/THF at room, wxone (5.0 g, excess) was added in water (20 ml). Reaction mixture was stirred at room temperature for 6 hrs and filtered. Methanol-THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography by eluting it with 4:1 ethyl acetate; hexane and 2-{[4-(2-butynyl oxy)phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide was isolated as a white solid. mp: 191° C.; Yield: 45 mg (24%); MS: 366.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 0.95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J=2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J=9.1 Hz, 1H), 4.87 (d, J=2.34 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.76 (d, J=9 Hz, 2H), 9.01 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:26]=[C:27]([S:31]([NH:34][CH2:35][C:36]5([C:40]([OH:42])=[O:41])[CH2:39][CH2:38][CH2:37]5)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[O:24])[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl[CH2:44][C:45]([N:47]([CH2:51][CH2:52][CH3:53])[CH2:48][CH2:49][CH3:50])=[O:46].C(=O)(O)[O-].[Na+].[Na+].[I-]>CN(C=O)C>[CH2:48]([N:47]([CH2:51][CH2:52][CH3:53])[C:45]([CH2:44][O:41][C:40]([C:36]1([CH2:35][NH:34][S:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:23]([N:20]3[CH2:21][CH2:22][C:15]4([NH:14]/[C:13](=[N:12]/[C:10]([C:3]5[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=5)=[O:11])/[NH:17][CH2:16]4)[CH2:18][CH2:19]3)=[O:24])[CH:26]=2)(=[O:32])=[O:33])[CH2:37][CH2:38][CH2:39]1)=[O:42])=[O:46])[CH2:49][CH3:50]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCC5(C(=O)O)CCC5)c4)CC3)N2)nc1Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)COC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)N3CCC4(CC3)CN/C(=N\C(=O)c3nc(Cl)c(N)nc3N)N4)c2)CCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 1-[(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-methyl]-cyclobutanecarboxylic acid (step 2) (350 mg, 0.564 mmol) in DMF (10 ml) was stirred at 50° C. with pre-activated molecular sieves for 30 min. 2-Chloro-N,N-dipropylacetamide (100 mg, 0.564 mmol), sodium bicarbonate (142 mg, 1.693 mmol) and NaI (8.46 mg, 0.056 mmol) were added and stirring continued at 50° C. After 3.5 h, the mixture was allowed to cool to RT and the molecular sieves were removed. The mixture was poured into water and the resulting white suspension was filtered, washed with water and dried in vacuo. The solid was dissolved in DCM and diethyl ether was added to yield a white precipitate which was collected by filtration and dried under vacuum overnight to afford the title product; 1H NMR (400 MHz, DMSO-d6) δ 9.30-7.74 (4H, br hump), 7.88 (1H, d), 7.79 (1H, br s), 7.69 (1H, dd), 7.66 (1H, m), 7.11-6.67 (1H, br hump), 6.84-6.61 (2H, br s), 4.76 (2H, s), 3.82-3.29 (4H, m), 3.44 (2H, s), 3.18-3.14 (4H, m), 3.15 (2H, br s), 2.31-1.95 (4H, m), 1.81 (2H, m), 1.83-1.65 (4H, m), 1.54-1.45 (4H, m), 0.86 (3H, t), 0.80 (3H, t); LC-MS Rt 3.62 mins; 761.7 [M+H]+, Method 10minLC_v003.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:11])=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A stirred solution of 8.3 grams (0.063 mole) of 2-amino-6-methylbenzonitrile in 125 mL of N,N-dimethylformamide was cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide was added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. After this time, the reaction mixture was poured into 1 liter of aqueous 3N sodium hydroxide. The mixture was then diluted to a volume of about 1700 mL with distilled water. A solid precipitate was collected by filtration and dried under reduced pressure, yielding 12.3 grams of 2-amino-5-bromo-6-methylbenzonitrile, mp 111°-113° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].O>N1C=CC=CC=1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH3:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulphonyl chloride (2.98 ml, 38.6 mmol) was added to an ice-cold solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (Synth. Commun. 1993; 23(17); 2443) (4.5 g, 25.7 mmol) in pyridine (40 ml), and the reaction stirred for 2 hours. The solution was poured into water (150 ml), and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with 10% aqueous citric acid solution, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (34:66 to 40:60) to give the title compound, 1.0 g.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])/[CH3:4].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])/[CH3:4])=[CH:20][CH:19]=1)[CH3:29]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C\COc1ccc(C(=O)O)cc1
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(/C)CCC=C(C)C)cc1
Yield: 30 %

Procedure:
In a manner identical to Example 15, 4-neryloxybenzoic acid (1.64 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.84ml), thereby yielding 0.69 g (30%) of the aimed compound.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([S:24][CH3:25])=[N:18][C:19]=2[NH2:23])(=O)C1C=CC=CC=1>CN>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([S:24][CH3:25])=[N:18][C:19]=2[NH2:23]
Reactant: CSc1nc(N)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Agent: CN
Product: CSc1nc(N)c2ncn(COCCO)c2n1

Procedure:
A mixture of 2.20 g (6.12 mmol) of 9-(2-benzoyloxyethoxymethyl)-2-methylthioadenine and 100 ml of 40% aqueous methylamine was heated on a steam bath with occasional agitation for one hour. The solution was cooled and spin evaporated in vacuo. The resultant oil was leached with five 40 ml portions of hot ether to give a solid; yield, 1.31 g (84%), m.p. 174°-176°. Recrystallization from ethanol gave the analytical sample of 9-(2-hydroxyethoxymethyl)-2-methylthioadenine; λmax (ε×10-3) (10% EtOH in solvent) pH 1-270 (16.7), 291 (sh) (11.9), H2O and pH 13-276 (15.2) nm; nmr (DMSO-d6), 2.49 (3H, S), 3.55 (4H, S), 4.65 (1H, br S), 5.55 (2H, S), 7.31 (2H, S), 8.15 (1H, S) δ.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([S:11][CH3:12])=[N:9][N:10]=1)=O)C.[NH3:13]>C(O)C>[CH3:12][S:11][C:8]1[S:7][C:6]([C:4]([NH2:13])=[O:3])=[N:10][N:9]=1
Reactant: CCOC(=O)c1nnc(SC)s1
Reactant: N
Solvent: CCO
Product: CSc1nnc(C(N)=O)s1

Procedure:
11.8 g of 5-methylthio-1,3,4-thiadiazole-2-carboxylic acid ethylester which is the compound obtained in Example 10, were mixed with 50 ml ethanol and 50 ml of a 25% aqueous ammonia solution whereupon the mixture was heated for 15 minutes on a steam bath. After cooling part of the reaction product precipitated. The precipitation was completed by adding ice water. The precipitate was then removed by suction and dried in a vacuum.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][C:16]([CH3:18])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:18][C:16]1([CH2:15][CH2:14][C:13]([OH:20])=[O:19])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: CC(=O)CCC(=O)O
Reactant: OCCC1=CCc2ccccc21
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(CCC(=O)O)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of indene-3-ethanol (15 g), dry benzene (300 ml), levulinic acid (22.6 g), boron trifluoride etherate (3 ml) and hydrated alkali-aluminum silicate (Molecular Sieves No. 4) is stirred at ambient temperature for 2 hr.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:14])[O:5][C:6]1[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]([F:12])=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: CCOC(=O)Oc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of the product from Example 47A (0.88 g, 4.03 mmol) in concentrated sulfuric acid (2 mL) cooled in an ice bath was added fuming nitric acid (0.27 mL, 6.45 mmol) slowly to maintain the temperature at 0° C. The mixture was stirred for an additional 2 hours, then ice water (10 mL) was added to the solution and the resultant solid was collected by filtration washed with water and dried in a vacuum oven to provide the title compound (0.87 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]1([N:23]2[C:27]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)=[CH:26][C:25]([CH:33]=O)=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:33][C:25]3[CH:26]=[C:27]([C:28]4[O:29][CH:30]=[CH:31][CH:32]=4)[N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: Clc1cccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)c1
Yield: 68.6 %

Procedure:
Compound 80 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH2:1]([C:4]1([CH2:11][CH2:12][CH3:13])[CH2:9][C:8](=[O:10])[O:7][C:5]1=[O:6])[CH2:2][CH3:3].[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH2:25][O:26][C:27]3[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=3)[NH2:30])=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH2:25][O:26][C:27]3[CH:28]=[C:29]([NH:30][C:8](=[O:10])[CH2:9][C:4]([CH2:11][CH2:12][CH3:13])([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])[CH:31]=[CH:32][CH:33]=3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1
Reactant: CCCC1(CCC)CC(=O)OC1=O
Product: CCCC(CCC)(CC(=O)Nc1cccc(OCc2ccc3ccc(F)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-dipropylsuccinic acid anhydride and 3-(7-fluoro-2-quinolinylmethoxy)aniline; beige crystals of m.p. 155°-156°.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])[CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][CH:15]=1
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1ncc(Br)s1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a suspension of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (Prepared in Example 1; 21 mg; 0.06 mmol) and N-bromosuccinimide (11 mg; 0.06 mmol) in anhydrous carbon tetrachloride (1.0 mL) was added benzoyl peroxide (1 mg; 0.004 mmol). The mixture was stirred at 95° C. in a sealed tube. After 1.5 h, N-bromosuccinimide (2 mg) and benzoyl peroxide (1 mg) were added and the mixture stirred for 30 min. further. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up into ethyl acetate and washed with water. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (Biotage 12S, eluent: 20% ethyl acetate/hexanes to give 15 mg (58%) of N-(5-Bromo-thiazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a grey foam: EI-HRMS m/e calcd for C20H23BrN3O2S (M+) 447.0616, found 447.0623.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]([Br:13])[CH3:10])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(F)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (±)-1-(3-bromo-5-fluorophenyl)ethanol (1.0 g, 4.6 mmol) and carbon tetrabromide (1.82 g, 5.48 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (1.44 g, 5.48 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with several volumes of pentane, and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (1% ethyl acetate/hexanes) to give 1.26 g (98%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.35 (s, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 5.06 (q, J=7.0 Hz, 1H), 2.00 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 163.6, 161.6, 147.2 (m), 126.0 (m), 122.8, 122.7, 119.2, 119.0, 113.3, 113.1, 46.5, 26.7.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].C(O)(=O)C.[Cl:16]N1C(=O)CCC1=O>O>[Cl:16][C:10]1[CH:9]=[C:6]([O:7][CH3:8])[C:4]([OH:5])=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: COc1cccc(C=O)c1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Cl)cc(C=O)c1O
Temperature: 105 °C
Reaction time: 0.12 h
Yield: 52 %

Procedure:
o-Vanillin (100.5 g, 660 mmol), acetic acid (504 mL) and N-chlorosuccinimide (83.8 g, 627 mmol) were mixed and heated to 105° C. over 30 minutes. A rapid exotherm from 55 to 105° C. occurred over 7 minutes. The mixture refluxed for a few minutes and was allowed to cool slowly to room temperature (2.5 h). Water (1 L, 2 volume equivalents) was added to the mixture slowly over 10 minutes. The mixture was stirred for 5 minutes, filtered and the crude product air dried to afford 146.9 g of wet cake as a light yellow powder with 90% product, 3% o-vanillin and 7% dichlorovanillin Recrystallization from 200 g ethanol afforded 61 g (52% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=2[CH:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH:21]=[CH:22][C:23]=2[CH:28]=1)=[O:30]
Reactant: O=C(O)c1ccc2occc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2occc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with benzofuran-5-carboxylic acid. MS: 404.4 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Br-:15].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:15][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[CH3:14])[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH2:7]2
Reactant: [Br-]
Reactant: Cc1ccc2c(c1)N(C(C)C)CCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)CCCN2C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
To a cooled solution of 7-methyl quinoline (5.00 g, 35 mmol) and nickel (II) chloride hexahydrate (1.40 g, 6 mmol) in methanol (130 mL) was added sodium borohydride (5.50 g, 140 mmol) portionwise. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Hydrochloric acid (2N, 200 mL) was added to the black residue and the mixture stirred at room temperature until disappearance of the black precipitate. The acidic solution was neutralized with concentrated ammonium hydroxide and extracted with ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered and evaporated to give 5.28 g of 7-methyl-1,2,3,4-tetrahydro-quinoline (100%), used without further purification. A mixture of 7-methyl-1,2,3,4-tetrahydro-quinoline (1.20 g, 8.2 mmol), potassium carbonate (2.3 g, 16.4 mmol) and isopropyl iodide (3.3 mL, 32.8 mmol) in N,N-dimethylformamide (10 mL) was heated at 60° C. with stirring for 24 hours. The solution was cooled to room temperature and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.28 g (82%) of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline. To a solution of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (1.04 g, 5.5 mmol) in dichloromethane was added tetrabutylammonium tribromide (2.65 g, 5.5 mmol) and the solution stirred at room temperature for 5 hours. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (ethyl acetate/hexane, 1:9) to give 1.00 g of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (67%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCc1ccccc1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccccc2)c(=O)[nH]c1=O
Yield: 72.5 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (285 mg, yield: 72.5%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11](C#N)([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[C:17](=[O:20])([O-])[O-:18].[K+].[K+]>Cl.O>[CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH3:13])([C:17]([OH:18])=[O:20])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)N1CC2CC(C)(C#N)CC2C1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C)(C(=O)O)CC2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
5-Cyano-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12b (6.99 g, 31.6 mmol) was dissolved in 90 mL of hydrochloric acid (36%). The reaction mixture was heated at 50° C. in an oil bath and stirred for 48 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was diluted with 100 mL of water. Upon cooling by an ice-water bath, the mixture was adjusted to pH 6 with potassium carbonate and extracted with ethy acetate (1500 mL×3) and dichloromethane (150 mL×3) successively. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2-dimethylcarbamoyl-5-methyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 12c (7.0 g, yield 92%) as a yellow liquid, which was directly used in the next step.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[CH3:14].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:2][CH:3]2[O:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4]2)[CH2:19]1)[CH3:14]
Reactant: CCOC(=O)CC1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (1.34 g, 5.84 mmol), piperidin-3-yl-acetic acid ethyl ester (1.0 g, 5.84 mmol) in acetonitrile (25 ml) was added K2CO3 (0.81 g, 5.84 mmol) and KI (0.97 g, 5.84 mmol). The reaction mixture was irradiated under microwaves at 82° C. for 8 h. Water (100 ml) was then added. The reaction mixture was extracted with DCM (3×50 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 95:5).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:20]([F:21])=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=3[F:22])[NH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[C:26]([NH2:34])[N:25]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:15]([F:22])=[CH:16][C:17]([NH:18][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[N:27]=[C:26]([NH2:34])[N:25]=4)=[CH:19][C:20]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]cc(C5CC5)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
330 mg (1.10 mmol) of 4-[(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoroaniline and 320 mg (1.64 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water and 2 ml of ethanol. 0.55 ml (2.2 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 1 h. Another 107 mg (0.55 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added, and the mixture is heated for a further 2 hours. The mixture is made alkaline by addition of 1N aqueous sodium hydroxide solution and extracted with ethyl acetate, and the organic phase is washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The product is purified by preparative HPLC.