Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].Br[CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>>[OH:38][CH:35]([CH2:36][OH:37])[CH2:34][N:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: OCC(O)CBr
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CC(O)CO)CC3)cc2)CC1
Yield: 71 %

Procedure:
By the same procedure as described in the example 23, synthesis was carried out starting with 1-[4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine and using 3-bromo-1,2-propanediol. Then, the product was recrystallized using isopropanol and isopropyl ether to give the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=O.[NH:6]([CH2:13][C:14]([O:16]CC)=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C1CCC(N=C=NC2CCCCC2)CC1.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[O:5]=[C:3]1[CH2:2][N:34]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[C:14](=[O:16])[CH2:13][N:6]1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(O)CBr
Reactant: NCCc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CN1CC(=O)N(CCc2ccncc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
A 25 mL round bottom flask was charged with bromoacetic acid (0.42g, 3.3 mmol), diethyl iminodiacetate (591 μL, 3.0 mmol) and 6 mL of DCM, followed by DCC (0.6809 g, 3.3 mmol). The mixture was stirred at room temperature for about one hour. The white solid DCU was filtered through a glass fritted funnel. The filtrate was concentrated in vacuo and diluted with 4.5 mL dichloromethane, followed by 4-(2-aminoethyl)pyridine (203 μL, 2.0 mmol). The resulting mixture was stirred at room temperature for 18 hour, diluted with DCM and washed with saturated NaHCO3. The aqueous layer was further extracted with DCM and all the organic layers were combined, dried (MgSO4), concentrated in vacuo and chromatographed through 80 g of silica gel eluting with 7% methanol in DCM to afford the title compound as a white solid (0.67 g, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8](Cl)[NH:9][C:5]=2[CH:4]=1.NC(N)=[S:15].Cl.[CH3:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:29]Cl)[CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>O.C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:15][CH2:29][C:27]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:28]=3[N:19]([CH3:18])[CH2:20][CH2:21][CH2:22]4)[NH:9][C:5]=2[CH:4]=1
Reactant: NC(N)=S
Reactant: CN1CCCc2cccc(CCl)c21
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(SCc3cccc4c3N(C)CCC4)[nH]c2c1
Yield: 83.1 %

Procedure:
5-Methoxy-2-chlorobenzimidazole (0.55 g), thiourea (0.2 g) and ethanol (10 ml) were refluxed for 2 hours. To the reaction mixture was added a solution of 1-methyl-8-chloromethyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.51 g) and sodium hydroxide (0.3 g) in water (5 ml) and the mixture was refluxed for 5 hours. After completion of the reaction, ethanol was distilled off and water was added to the resulting residue, and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, chloroform was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate (4:1)] to give 8-(5-methoxy-2-benzimidazolyl)thiomethyl-1-methyl-1,2,3,4-tetrahydroquinoline (0.62 g).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[NH:4])=[O:3].[I:13][C:14]1[C:15]([NH2:23])=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19](O)=[O:20].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:23][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:4]=[S:2]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:1])=[O:3])=[O:20])=[CH:22][C:14]=1[I:13]
Reactant: Nc1ncc(C(=O)O)cc1I
Reactant: COC(=O)CCCCS(C)(=N)=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Temperature: 70 °C
Yield: 50.3 %

Procedure:
A solution of methyl 5-(S-methylsulfonimidoyl)pentanoate (2.32 g) was dissolved in anhydrous DMF (30 mL) and to this solution was added 5-iodo-6-amino-nicotinic acid (3.17 g, ˜1 eq), diisopropylethylamine (4.2 mL, 2 eq), and BOP (5.85 g, 1.1 eq). The reaction mixture was heated at 70° C. for 1 hour and then partitioned between EtOAc and aq NH4Cl. The organic layer was separated, washed sequentially with aq NH4Cl (1×), saturated aq NaHCO3 (1×), brine (1×), and dried with anhydrous Na2SO4 overnight. The upper solution layer was decanted, concentrated, and the brown oily reside was subject to column chromatography (acetone-CHCl3 1:100 to MeOH-acetone-CHCl3 1:2:50). Concentration of the product eluting fractions provided the title compound as a slight yellow colored foam (2.65 g).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:38][C:39]1[CH:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:42]=[CH:43][CH:44]=1.C(N(CC)CC)C>C(#N)C.CO>[N:1]1([CH2:10][C:11]([NH:38][C:39]2[CH:40]=[C:41]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:42]=[CH:43][CH:44]=2)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)Cn1cnc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Cn1cnc2ccccc21)Nc1cccc(-c2ccccc2)c1
Yield: 19.4 %

Procedure:
(1H-Benzimidazol-1-yl)acetic acid (triethylamine salt) (315 mg, 1.1 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflurophosphate (520 mg, 1.4 mmol), 3-amino biphenyl (290 mg, 1.6 mmol) and triethylamine (0.6 mL, 4.4 mmol) in acetonitrile (10 mL) was stirred at room temperature for 24 h. Methanol (10 mL) was then added and evaporated to dryness in vacuo. The crude mixture was then passed through a silica gel column eluting with ethyl acetate:methanol (1% up to 3% methanol). The product was collected and dried, dissolved in methanol and 1 M hydrogen chloride in diethyl ether (0.5 mL) added and product crystallised, filtered and dried to give the title compound as a white solid (70 mg, 17%). 1H NMR (400 MHz, CD3OD+1 drop of DMSO-d6) δ ppm 5.55 (2H, s), 7.32-7.35 (1H, m), 7.40-7.44 (4H, m), 7.56-7.59 (3H, m), 7.67-7.72 (2H, m), 7.89-7.96 (3H, m), 9.54 (1H, s). MS (ES) m/z 327.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16](=[S:18])[NH2:17])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26]([C:28]1[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:30][CH:29]=1)=O.O>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:18][CH:25]=[C:26]([C:28]3[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=[CH:30][CH:29]=3)[N:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=S)c2c1oc1ccccc12
Reactant: CCOC(=O)c1cccc(C(=O)CBr)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(-c2csc(-c3ccc(OC)c4oc5ccccc5c34)n2)n1
Reaction time: 20 h
Yield: 28 %

Procedure:
To a stirred solution of 4-methoxydibenzo[b,d]furan-1-carbothioamide (140 mg, 0.544 mmol) in ethanol (5 mL) was added sodium bicarbonate (60 mg, 0.714 mmol) and ethyl 6-(2-bromoacetyl)picolinate (150 mg, 0.551 mmol). The stirring was continued at room temperature for 20 hours. The reaction mixture was poured into the water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated at reduced pressure to give the product, which was purified by column chromatography by using a gradient of ethyl acetate in hexane (0-6%). Yield—28%; Rf 0.5 (Ethyl acetate:Hexane (3:7); HPLC (purity): 98.1%; 1H-NMR (CDCl3) δ: 1.48-1.57 (m, 3H), 4.14 (s, 3H), 4.50-4.55 (m, 2H), 7.07 (d, 1H), 7.49-7.53 (m, 1H), 7.65-7.69 (m, 2H), 7.94-7.98 (m, 1H), 8.09 (d, 1H), 8.42 (s, 1H), 8.47 (d, 1H), 8.73 (d, 1H); MS m/z: 431.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:9]/[NH:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1>N1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:10]=[N:9][CH:8]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N/N=C/c2cc(Br)ccn2)cc1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: Brc1ccn2nncc2c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A solution of (E)-N′-((4-bromopyridin-2-yl)methylene)-4-methylbenzenesulfonohydrazide (compound 40.1, 3.8 g, 10.7 mmol) in morpholine (12 mL) was heated at 130° C. for 3 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (150 mL) and washed with water (2×30 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 4:1) to yield 2.10 g (99%) of the title compound as a light yellow solid. m/z (ES+) 198, 200 (M+H)+.
Reaction SMILES: [C:1]([NH2:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([N:15]([CH2:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]([NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:18][CH:17]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CCCCCCCCCC(N)=O
Product: CCCCCCCCCC(=O)NC(NC(=O)CCCCCCCCC)c1ccc(N(CC)CC)cc1
Yield: 56 %

Procedure:
Compound 55 was prepared from decanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 56%. 1H NMR (400 MHz, DMSO) δ 8.99 (d, J=9.6 Hz, 1H), 8.38 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.58 (d, J=8.4 Hz, 2H), 5.84 (d, J=8.4 Hz, 1H), 3.27-3.30 (m, 4H), 2.33 (t, J=7.2 Hz, 4H), 2.14 (t, J=7.2 Hz, 4H), 1.50-1.55 (m, 4H), 1.24-1.28 (m, 24H), 1.06 (t, J=7.2 Hz, 6H), 0.87 (t, J=7.2 Hz, 6H). LC-MS (ESI): m/z 502.4 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.C([C:30]([CH3:32])=[O:31])C(C)C.N([C:42](C)(CC)[C:43]([O-:45])=O)=NC(C)(CC)C([O-])=O>CCCCCCC>[C:1]([O:6][CH:7]([O:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.[CH3:7][O:6][CH2:1][CH2:2][O:45][CH2:43][CH2:42][O:31][CH2:30][CH3:32]
Reactant: CC(=O)CC(C)C
Reactant: CCC(C)(N=NC(C)(CC)C(=O)[O-])C(=O)[O-]
Agent: C=C(C)C(=O)OC(C)OC1CCCCC1
Agent: C=Cc1ccc(OC)cc1
Solvent: CCCCCCC
Product: CCOCCOCCOC
Reaction time: 6 h

Procedure:
Into a 500 ml-volume three-neck flask, 63.7 g (0.30 mol) of 1-cyclohexyloxyethyl methacrylate, 40.3 g (0.30 mol) of p-methoxystyrene and 300 ml of methyl isobutyl ketone were charged. A catalytic amount of 2,2′-azobis(methyl 2-methylpropionate) was added thereto as a radical polymerization initiator, and polymerization was allowed to proceed at 80° C. for 6 hours in a nitrogen stream. The reaction solution was cooled and then poured in a large amount of heptane to precipitate a polymer. The crystal was collected by filtration and dissolved in diethylene glycol ethyl methyl ether, and heptane and methyl isobutyl ketone contained in the solution were removed by distillation under reduced pressure to obtain Polymer A1-6 (1-cyclohexyloxyethyl methacrylate/p-methoxystyrene) as a diethylene glycol ethyl methyl ether solution.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:18][N:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cn1
Reactant: ClCc1ccccn1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cn1

Procedure:
The title compound was prepared from N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5 -hydroxypyridine-2-carboxamide and 2-chloromethyl-pyridine hydrochloride according to the method described for Example 4; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.40 (s, 2H), 7.33 (m, 1H), 7.39 (m, 1H), 7.58 (m, 2H), 7.72 (m, 1H), 7.88 (m, 1H), 8.13 (m, 1H), 8.21 (m, 1H), 8.36 (m, 1H), 8.51 (m, 1H), 8.61 (m, 1H), 10.14 (s, 11H); Mass Spectrum: M+H+ 403.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.O1[CH2:42][CH:19]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]3[O:41][CH2:40]3)=[CH:33][CH:32]=2)([CH3:30])[CH3:29])=[CH:24][CH:23]=1.[OH-:43].[K+]>CO>[OH:43][CH:19]([CH2:42][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]([OH:41])[CH2:40][N:6]3[C:5](=[O:10])[C:4]4([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]4)[NH:8][C:7]3=[O:9])=[CH:33][CH:32]=2)([CH3:29])[CH3:30])=[CH:26][CH:27]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COc1ccc(C(C)(C)c3ccc(OCC(O)CN4C(=O)NC5(CC(C)(C)N(C)C(C)(C)C5)C4=O)cc3)cc1)C2=O

Procedure:
26.3 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 17.0 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane and 0.5 g of potassium hydroxide were added to 200 ml of methanol, and the mixture was refluxed for 8 hours. After completion of the reaction, the mixture was allowed to cool and the crystals which precipitated were washed with methanol and then recrystallized from benzene to give Compound No. 2 in the form of white crystals melting at 241°-244° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:11]1[C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:15][C:14]=2[NH:13][CH:12]=1)[CH3:3]
Reactant: C=O
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2cc(Cl)ccc12
Reaction time: 16 h
Yield: 95 %

Procedure:
Glacial acetic acid (0,4 ml) was added dropwise to an aqueous solution at 33% (w/v) of dimethylamine (0,4 ml), cooled in an ice bath, at a speed so as not to exceed a temperature of 5° C. Under continuous stirring and in an ice bath, were added in succession an aqueous solution of formaldehyde (0,2 ml at 40% w/v) and then 420 mg of 6-chloroindole, which in approximately 10 minutes dissolved in the reaction mixture with the development of heat. The reaction mixture was left at room temperature for approximately 16 hours. The solution was then poured into NaOH 2N (10 ml) and extracted with ethyl ether (3×15 ml). The organic phase was washed with saturated NaCl/H2O (2×10 ml) and dried on anhydrous magnesium sulphate overnight. On evaporation of the solvent, a residue was obtained, of practically pure 6-chloro-gramine, equal to 550 mg (yield 95%).
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Br:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 158-160° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.85 (s, 1 H), 4.80-4.75 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=8.1 Hz, 2 H), 1.88-1.74 (m, 2 H), 1.70-1.60 (m, 2 H), 0.88 (t, J=7.3 Hz, 6H); HRMS (ESI) calcd for C17H19N3OBrCl2 (M+H)+: 430.0089; found m/z 430.0109.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2([CH3:24])[C:19](=[O:20])[C:18]3[C:13](=[C:14]([Br:22])[CH:15]=[C:16]([Br:21])[CH:17]=3)[NH:12][C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([C:10]2([CH3:24])[C:19](=[O:20])[C:18]3[C:13](=[C:14]([Br:22])[CH:15]=[C:16]([Br:21])[CH:17]=3)[NH:12][C:11]2=[O:23])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C2(C)C(=O)Nc3c(Br)cc(Br)cc3C2=O)cc1N
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(O)c(N)c2)C(=O)Nc2c(Br)cc(Br)cc2C1=O
Yield: 51.8 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(3-amino-4-methoxy-phenyl)-6,8-dibromo-3-methyl-1H-quinoline-2,4-dione (36 mg, 0.079 mmol) and BBr3(0.4 mL, 1.0 M solution in dichloromethane). After normal workup, the pure objective compound (18 mg, 52%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=3:1): 1H NMR (200 MHz, CDCl3) δ 1.64 (s, 3H, CH3), 4.85 (br s, 3H, NH2 & OH), 6.41 (d, J=2.4 Hz, 1H, ArH), 6.37 (dd, J=8.6, 2.4 Hz, 1H, ArH), 6.55-6.61 (m, 2H, ArH), 7.86 (d, J=2.0 Hz, 1H, ArH); HRMS m/e cacld. for C16H12N2O3Br2 437.9215, found 437.9211.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.[CH2:35](N1C[C@H]2C(N)CC[C@H]2C1)[C:36]1C=CC=CC=1>>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]([NH:29][C@@H:26]2[C@H:24]3[C@H:23]([CH2:22][N:21]([CH2:20][C:19]4[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=4)[CH2:25]3)[CH2:28][CH2:27]2)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:36][CH:35]=1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by substituting 2,2-diphenylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50 (s, 1H), 7.71 (d, J=7.5, 2H), 7.63 (d, J=7.2, 2H), 7.45 (d, J=7.4, 2H), 7.39-7.28 (m, 5H), 7.25 (dd, J=5.8, 8.9, 3H), 4.51-4.42 (m, 1H), 3.44 (d, J=13.3, 1H), 3.25 (d, J=13.3, 1H), 2.85 (qd, J=3.2, 7.9, 1H), 2.59 (dd, J=3.4, 9.5, 1H), 2.47-2.37 (m, 1H), 2.26 (t, J=8.3, 1H), 2.21-2.13 (m, 2H), 1.85-1.76 (m, 1H), 1.67-1.52 (m, 3H), 1.27-1.18 (m, 1H); MS (ESI+) m/z 479 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.F[C:21]1[CH:22]=[C:23](O)[CH:24]=[C:25](F)[CH:26]=1.ClC1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=1>>[O:19]([CH2:18][C@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:1]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=3)[CH2:9][C@@H:10]2[CH2:17][CH2:16]1)[C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CO)CC[C@H]2C1
Reactant: Clc1ccc(Cl)nc1
Product: Clc1ccc(N2CCN3C[C@H](COc4ccccc4)CC[C@H]3C2)nc1

Procedure:
A mixture of (7R,9aS)-N-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (WO 93/25552) and 3,5-difluorophenol were coupled followed by N-BOC deprotection according to Preparation 9. The product from this reaction was coupled with 2,5-dichloropyridine according to Preparation 11 to give the title compound. mp (—HCl) 260-261° C. HRMS calcd for C20H22ClF2N3O: 393.1419, found: 393.1410.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:27])[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[NH:23])[CH2:16][CH2:17][C:12]=3[C:11]([C:28]([F:31])([F:30])[F:29])=[N:10]2)=[CH:5][CH:4]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][N:24]([CH3:25])[C:22](=[N:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:28]([F:31])([F:29])[F:30])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=N)N(C)C)CC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCCC(=NS(C)(=O)=O)N(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
5-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-N,N-dimethyl-pentanamidine (0.050 g, 0.114 mmol) was dissolved in methylene chloride (10 mL). Methanesulfonyl chloride (0.1 mL, excess) and triethylamine (0.3, excess) were added to the reaction. The reaction was stirred at rt overnight, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes as the eluent followed by a methanol flush. Further purification by reverse phase HPLC and freeze-drying afforded the title compound (0.120 g, 74%): 1H NMR (CHCl3) δ 7.44 (d, j=8.7 Hz, 2H), 6.95 (d, j=8.8 Hz, 2H), 3.84 (s, 3H), 3.69 (t, j=7.0 Hz, 2H), 3.52 (t, j=6.3 Hz, 2H), 3.03 (s, 3H), 3.00(s, 3H), 2.99 (s, 3H), 3.14–2.98 (m, 2H), 2.89 (t, j=7.7 Hz, 2H), 1.75–1.62 (m, 2H) ppm; Mass Spec 516.3(M+H)+.