Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.C(N(CC)CC)C>[Pd].CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:4]2[N:5]=[C:6]([NH:8][NH2:9])[N:7]=[CH:2][N:3]=2)=[CH:12][C:13]=1[C:18]([F:19])([F:20])[F:21]
Reactant: NNc1nc(Cl)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: NNc1ncnc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Reaction time: 72 h
Yield: 44.4 %

Procedure:
A mixture of compound XXII (1.5 g, 0.005 mol), triethylamine (1.41 g, 0.014 mol) and palladium on carbon (10% w/w) (0.45 g) in methanol (100 mL) was purged with nitrogen, and then shaken in a Par apparatus under an atmosphere of hydrogen gas (45 psi pressure) for 3 days. The mixture was purged with nitrogen, concentrated in vacuo to a volume of ca. 20 mL, diluted with water (50 mL) and ethyl acetate (100 mL). The biphasic mixture was filtered to remove the catalyst and the organic phase separated, rinsed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford the titled compound XXIII as a white solid (0.64 g, 48% yield, crude): m.p. 181-182° C.; ESI/MS 289 (M+H) 287 (M−H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][NH:15][CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1.[CH2:19]=O.[BH4-].[Na+]>CO.CCOCC.Cl>[ClH:2].[Cl:2][C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@H:9]3[CH2:14][N:15]([CH3:19])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[C:5]([CH2:17][CH3:18])[CH:4]=1
Reactant: C=O
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCc1cc(Cl)c2c(c1)[C@H]1CN(C)C[C@@H]1NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 142.3 %

Procedure:
To a solution of (3aR,9bS)-6-chloro-8-ethyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one hydrochloride (Example 29) (20 mg, 0.07 mmol) in 2 mL of methanol was added formaldehyde (0.017 mL of 37% aqueous solution, 0.21 mmol) followed by sodium borohydride (14 mg, 0.35 mmol) portionwise. The reaction mixture was stirred at ambient temperature for 1 h. The reaction was concentrated and the residue was purified (ISCO, elution with 0-15% methanol/methylene chloride) to afford the free base. To the free base in 1 mL of ether was added two drops 12 N HCl. The mixture was concentrated in vacuo, triturated with ether, and dried in vacuo to afford 15 mg (71%) of the title compound of Example 62 as an off-white solid. 1H NMR (CD3OD): 7.35 (s, 1H), 7.00 and 6.97 (s, 1H), 4.07-4.02 (m, 1H), 3.91-3.85 (m, 1H), 3.74-3.69 (m, 1H), 3.61-3.55 (m, 1H), 3.45-3.28 (m, 2H), 3.14 and 3.08 (s, 3H), 2.69 (q, 2H), 1.25 (t, 3H). LRMS (ESI): 265.2/267.2 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]O)#[N:21].[Br:33]N1C(=O)CCC1=O>C1COCC1>[Br:33][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:24]=1[O:23][CH2:22][C:20]#[N:21]
Reactant: Cc1cccc(CO)c1OCC#N
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(CBr)c1OCC#N
Temperature: 0 °C

Procedure:
Triphenylphosphine (15.2 g, 57.8 mmoles) is added to 2-cyanomethoxy-3-methylbenzylalcohol (9.3 g, 52.5 mmoles, example 23) in THF (175 mL). The mixture is stirred until homogeneous and cooled to 0° C., followed by addition, in three portions, of N-bromosuccinimide (10.3 g, 57.8 mmoles). After 90 minutes the reaction is concentrated and the residue purified by column chromatography (silica, 5:1 hex: EtOAc) to yield the title compound as a pale yellow crystalline solid. MS (EI) 239, 241 (M)+, Br pattern.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:34]>C(OCC)(=O)C>[ClH:34].[NH2:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:14]=2
Reactant: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3cccs3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(=O)n(CC(C)C)c(CN)c(-c3cccs3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate (0.14 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diisopropyl ether to give methyl 3-(aminomethyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylate hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)CCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:35]1[CH:36]=[CH:37][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)=[CH:33][CH:34]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccncc5)cc4)CC3)C2)c2ccccc21
Yield: 13 %

Procedure:
A mixture of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (25 mg, 0.061 mmol), 4-(tributylstannyl)pyridine (24 mg, 0.067 mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.003 mmol), tri-tert-butylphosphine (1.5 mg, 0.007 mmol), and potassium fluoride (12 mg, 0.20 mmol) in tetrahydrofuran (0.3 ml) was microwave irradiated at 90° C. for 15 minutes. Then the desired product was obtained from the mixture by prep-HPLC (3.2 mg, yield: 13%). LCMS: m/z 411.1 (M+H)+; 433.0 (M+Na)+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[CH3:13][C:4]1[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[C:2]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(I)cn1-c1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccccc2)c(C)n1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
4-Iodo-2-methyl-1-phenyl-1H-imidazole (0.55 g, 1.94 mmol) was dissolved in 9 mL of anhydrous THF and isopropylmagnesium chloride (2 M THF solution, 1.2 mL, 2.4 mmol) was added dropwise. The reaction was stirred for more than 1 h at room temperature. Tributylstannyl chloride (0.55 mL, 2.03 mmol) was slowly added. After the reaction was judged to be complete by TLC, NH4Cl solution and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (triethylamine/ethyl acetate/hexanes) to give 0.2 g (23%) of 2-methyl-1-phenyl-4-tributylstannanyl-1H-imidazole.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1.[Li]CCCC.C[O:17][B:18](OC)[O:19]C>Cl.C(OCC)(=O)C>[F:10][C:4]1[CH:3]=[CH:2][C:9]([B:18]([OH:19])[OH:17])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: COB(OC)OC
Reactant: OCc1ccc(Br)cc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: OCc1cc(B(O)O)ccc1F
Temperature: 21 °C
Reaction time: 0.42 h

Procedure:
To a solution of 4-bromo-2-fluoro-benzyl alcohol (10 g, 49 mmol) in TBF (500 mL) at −78° C. was added BuLi (2.5M, 43 mL, 107 mmol) dropwise keeping the internal temperature below −73° C. After 25 min., trimethylborate (25 mL, 107 mmol) was added and the resulting reaction mixture stirred for 15 h at −78° C., 1 h at 21° C., then diluted with HCl 10% and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. The residue was solidified from hexane/ethyl acetate with water (5 drops) to afford the 4-fluoro-3-hydroxymethyl-benzene-boronic acid compound as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:15](#[N:19])[CH2:16][C:17]#[N:18]>>[NH2:18][C:17]1[O:4][C:5]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=2[C:7](=[O:8])[C:16]=1[C:15]#[N:19]
Reactant: N#CCC#N
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)Cl
Product: N#Cc1c(N)oc2ccc(Cl)cc2c1=O

Procedure:
-- In the same way as described in Example 3, 2-acetoxy-5-chlorobenzoyl chloride and malononitrile are reacted to give crystals, mp 340°C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=[O:24])[CH:18]=2)[C:3]=1[C:4]#[N:5].[OH-].[Na+:27]>>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]([O-:25])=[O:24])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[N:9]=1.[Na+:27]
Reactant: N#Cc1c(-c2cccc(C(=O)O)c2)cc(-c2ccccc2O)nc1N
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(-c2cccc(C(=O)[O-])c2)cc(-c2ccccc2O)nc1N
Yield: 95 %

Procedure:
2-amino-6-(2-hydroxyphenyl)-4-(3-hydroxycarbonyl-phenyl)nicotinonitrile (0.02 g, 0.045 mmol) was dissolved in 4N NaOH solution (2 mL), and the resulting solution was purified by HPLC (ODS reverse phase column, 10% CH3CN/H2O-90% CH3CN/H2O) to give Sodium 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]benzoate as a pale yellow powder (0.015 g, 95%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH:5]=[CH:6][CH:7]=[O:8].[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH:5]=[CH:6][CH2:7][OH:8]
Reactant: COC(CC=CC=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COC(CC=CCO)OC

Procedure:
reducing 5,5,-dimethoxypent-2-enal with diisobutylaluminum hydride to form 5,5-dimethoxypent-2-en-1-ol;
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]([CH3:14])=[C:4]2[S:5][CH:6]=[CH:7][C:3]=12.C([Li])(C)(C)C.[CH3:20][Sn:21](Cl)([CH3:23])[CH3:22]>O1CCCC1>[CH3:14][C:8]1[C:4]2[S:5][C:6]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][C:3]=2[C:2]([CH3:1])=[C:10]2[S:11][C:12]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:13][C:9]=12
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1c2ccsc2c(C)c2ccsc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c2cc([Sn](C)(C)C)sc2c(C)c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A dry 250-mL three-neck round bottom flask was flushed with N2 and was charged with 4,8-dimethylbenzo[1,2-b:4,5-b′]dithiophene (1.02 g, 4.70 mmol) and anhydrous tetrahydrofuran (THF) (75.0 mL, 0.01 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyllithium in hexanes (9.00 mL, 23.0 mmol) was added drop-wise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. A 1 M solution of trimethyltin chloride (19.0 mL, 37.0 mmol) in hexanes was added to the reaction flask dropwise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (10 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 50 mL of cool water and extracted with MTBE (100 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a THF solution to yield white solid (1.90 g, 74%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1>O1CCOCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1ccc2cnccc2c1
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCN(CCc1c[nH]c3ccccc13)C2

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.48 g, 20 mmol) and isoquinoline (5.33 g, 40 mmol) in abs. dioxan (50 mL) was stirred for 6 h at 80° C. The solvent was then removed in a vacuum, the residue mixed with CHCl3 (100 mL) and washed twice with water. The organic phase was dried over Na2SO4, concentrated to low volume in a vacuum, and the remaining residue purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:22][CH2:21]1
Reactant: OCCN1CCNCC1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCN(CCO)CC1)c1ccccc1-2
Yield: 36.4 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (3.0 g, 12.8 mmol) was reacted with N-(2-hydroxyethyl)piperazine (3.66 g, 28.2 mmol) as described in example 18. The crude product was purified by dissolving in aqueous NaHCO3 /NaOH and precipitated by adding to hydrochloric acid. The procedure was repeated and the product was finally washed with ethanol and dried to give 1.53 g (28%) of the title compound as a dihydrochloride. M.p. 210° C. (destruction). 1H-NMR (DMSO-d6 +D2O, δ): 2.35-3.6 (m, 10H), 3.75 (m, 2H), 4.73 (s, 1H), 7.22 (t, 1H), 7.35 (t, 1H), 7.51 (d,1H), 7.57 (d, 1H).
Reaction SMILES: FC1C=CC([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=CC=1.CN(C)[C@@H]1CCN(C(C2C=C(C)NC=2C=O)=O)C1>C(O)C.N1CCCCC1>[NH:12]1[C:13]2[C:9](=[CH:8][CH:16]=[CH:15][CH:14]=2)[CH2:10][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Agent: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[3-(3R)dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]44-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.9, 56%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(N3CCNCC3)ccn2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 182, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[CH2:10][N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[CH2:10][N:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2cccc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CN1CCNCC1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(2-(3-chlorophenylamino)-2-oxoethyl)piperazine-1-carboxylate (0.061 g, 0.17 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h, then the solvents were removed under reduced pressure to afford N-(3-chlorophenyl)-2-(piperazin-1-yl)acetamide trifluoroacetate salt (an oily material) that was dried in vacuo. To a mixture of this material (supposedly 0.17 mmol) and isopropanol (3.5 ml) was added 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) followed by diisopropylethylamine (0.14 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 15% ethyl acetate in dichloromethane. The title compound was obtained as an orange solid (0.040 g, 56%). 1H-NMR (500 MHz, DMSO-d6) 2.65 (br s, 4H, piperazine N(CH2)2), 3.14 (br s, 4H, piperazine N(CH2)2), 3.21 (s, 2H, NCH2CO), 6.95 (s, 2H, NH2), 7.11 (dd, J=7.94, 1.23 Hz, 1H) and 7.54 (dd, J=8.29, 0.98 Hz, 1H) (4-ArH and 6-ArH), 7.34 (t, J=8.07 Hz, 1H, 5-ArH), 7.84 (t, J=1.80 Hz, 1H, 2-ArH), 8.07 (s, 1H, 6-H), 9.91 (s, 1H, CONH);
Reaction SMILES: [O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:13][C@@H:12]1[OH:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(O)(C)C>CC(C)=O>[O:1]=[C:2]([CH2:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:14]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:13][C:12]1=[O:39])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC#CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC#CCC(C)[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
The solution of 396 mg of (13E)-(9S,11R,15S,16RS)-6-oxo-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16-methyl-18,18,19,19-tetradehydro-13-prostenoic acid in 8 ml of absolute dimethylketone was cooled, with exclusion of moisture, to -30° C., was mixed with 270 microliters of Jones solution and stirred for 1.5 h at -30° C. to -20° C. After addition of 2 ml of isopropanol, it was poured onto 50 ml of ice water, extracted several times with a total of 100 ml of diethyl ether, washed neutral with saturated sodium chloride solution, dried on magnesium sulfate, filtered and concentrated by evaporation in a vacuum. The colorless raw oil was chromatographed on plates coated with silica gel with hexane-ethyl acetate. Besides the initial material, 160 mg (41%) of the title compound was isolated as colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:15][CH2:16]Cl)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].[I:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:34])=[C:31]([CH:33]=1)[NH2:32]>C1(O)CCCCC1>[I:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:34])=[C:31]([N:32]2[CH2:16][CH2:15][N:4]([S:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:3][CH2:2]2)[CH:33]=1
Reactant: Cc1ccc(I)cc1N
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OC1CCCCC1
Product: Cc1ccc(S(=O)(=O)N2CCN(c3cc(I)ccc3C)CC2)cc1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
9.97 g of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (30.3 mmol) and 5.03 g of potassium iodide (30.3 mmol) in 75 mL of cyclohexanol were stirred for 1 h at 80° C. After addition of 7.7 g of sodium carbonate (72.7 mmol) and 5.65 g of 5-iodo-2-methyl-aniline (24.2 mmol), stirring continued for 8 h at 160° C. At room temperature, the mixture was filtered, washed with dichloromethane, and the filtrate evaporated to dryness. The residue was dissolved in dichloromethane, filtered, and the solvent evaporated. The remaining residue was trituated with n-heptane and the crystalline product filtered off, washed several times with n-heptane and dried in vacuo to yield 10.7 g of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22])[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15](=[O:17])[CH:16]=2)[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[C:20]=1[O:21][CH3:22]
Reactant: COc1cc(C(=O)Oc2ccccc2C(C)=O)cc([N+](=O)[O-])c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(-c2cc(=O)c3ccccc3o2)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 2.0 g of o-acetylphenyl 3,4-dimethoxy-5-nitrobenzoate in 12.5 ml of glacial acetic acid is treated with 0.94 g of sodium acetate and held at the reflux temperature for 4 hours. After cooling the mixture is poured into ice-water. The separated crystals are filtered under suction. After recrystallization from ethyl acetate/hexane there is obtained 2-(3,4-dimethoxy-5-nitrophenyl)-4H-1-benzopyran-4-one in the form of colorless crystals of m.p. 216°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:16][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:14]=[C:13]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[N:12]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Product: COc1ccc(Nc2nc(Cl)nc(Nc3ccc(Cl)cc3)n2)cc1
Yield: 62 %

Procedure:
The reaction of (4-chloro-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine with p-anisidine, according to method 2, gave 6-chloro-N-(4-chlorophenyl)-N′-(4-methoxyphenyl)-[1,3,5]triazine-2,4-diamine (51 mg, 62%): 1H NMR (CDCl3) 7.21–7.50 (6 H, m), 6.91 (2 H, d, J=11 Hz), 3.85 (3 H, s).