Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])[CH:18]=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=1)=[O:13].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(Cl)Cl>C(O)(C)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:27]([F:29])([F:30])[F:28])[CH:18]=[C:19]([NH:21][S:22]([CH2:25][CH2:26][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:24])=[O:23])[CH:20]=1)=[O:13]
Reactant: C1CCNCC1
Reactant: C=CS(=O)(=O)Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc(C(F)(F)F)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Nc1cc(NS(=O)(=O)CCN2CCCCC2)cc(C(F)(F)F)c1)c1c[nH]c2ccccc2c1=O
Temperature: 75 °C

Procedure:
A mixture of 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μL, 1.6 eq) and LiClO4 (20 mg, 1.7 eq) was suspended in a 1:1 solution of CH2Cl2: isopropanol (1.5 mL). The mixture was refluxed at 75° C. for 18 h. After this time, LCMS analysis showed >95% conversion to the desired product. The crude mixture was purified by reverse-phase HPLC to provide 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, 25%). 1H-NMR (d6-Acetone, 300 MHz) δ 8.92 (br s, 1H), 8.4 (d, J=8.1 Hz, 1H), 8.05 (br s, 1H), 7.94 (br s, 1H), 7.78 (br s, 2H), 7.53-751 (m, 1H), 7.36 (br s, 1H), 3.97 (t, J=7.2 Hz, 2H), 3.66 (t, J=8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H); ESI-MS 489.1 m/z (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[C:20]([CH:24]=1)[C:21]([NH:2][C@H:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4])=[O:22]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1c(F)cccc1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2c(F)cccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5) and 5-chloro-2-(2,6-difluorophenoxy)benzoic acid (step 4): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.83–7.74 (1H, m), 7.45 (2H, d, J=8.4 Hz), 7.35–7.23 (2H, m), 7.16–7.04 (2H, m), 6.67–6.61 (1H, m), 5.48–5.33 (1H, m), 3.90 (3H, s), 1.59 (3H, d, J=7.0 Hz)); MS (ESI) m/z 446 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:3]=12.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:26][NH:27][C:28]([NH2:30])=[S:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:13])=[CH:10][C:3]=12
Reactant: NNC(N)=S
Reactant: O=C(O)c1cc2c(Cl)cncc2s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1cc2c(Cl)cncc2s1
Temperature: 70 °C

Procedure:
4-Chlorothieno[2,3-c]pyridine-2-carboxylic acid (4.2 g, 19.7 mmol) was dissolved in 110 mL DMF in a round bottom flask. To this flask was added CDI (7.68 g, 47.4 mmol). After the flask was heated at 70° C. for 30 minutes, thiosemicarbazide (4.32 g, 47.4 mmol) dissolved in 5 mL DMF was added and the resulting mixture was heated at 70° C. for 30 minutes. After removing the DMF under reduced pressure, the remaining residue was mixed with 50 mL 1N HCl. After filtration and washing with water, the product was dried in a vacuum oven at 80° C. for 4 hours. The resulting product (6.0 g) was used directly in the next step. LCMS (API-ES) m/z (%): 287.1 (100%, M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]1=[O:13].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:7]1=[O:13]
Reactant: BrCCc1ccccc1
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Solvent: CC#N
Product: O=c1cc(OCCc2ccccc2)ccn1Cc1cccc(F)c1
Yield: 56.5 %

Procedure:
According to Scheme 13 Method A: The title compound was prepared from 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1 eq, 0.23 mmol, 0.05 g, Example 19 Step 2) and 1-(2-bromoethyl)benzene (2 eq, 0.46 mmol, 0.06 mL) according to the procedure described for Example 1 Step 2. Microwave conditions: 180° C. for 900s in acetonitrile (2 mL). The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 and by recrystallization in pentane to afford 1-(3-fluorobenzyl)-4-phenethoxypyridin-2(1H)-one (0.13 mmol, 43 mg, 58%) as a white solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([NH:17][C:18]([CH2:20][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:32]([O:34][CH3:35])=[O:33])=[C:26]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=1)=[S:19])=[O:16])[CH3:13].[CH3:36][O:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C:47](OC2C=CC=CC=2)=[O:48])[N:39]=1>C(#N)C>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([O:37][CH3:36])[N:39]=[C:40]([NH:46][C:47]([NH:31][S:28]([C:26]2[CH:27]=[C:22]([NH:21][CH2:20][C:18]([NH:17][C:15]([O:14][CH2:12][CH3:13])=[O:16])=[S:19])[CH:23]=[CH:24][C:25]=2[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:30])=[O:48])[N:41]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(N)(=O)=O)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1.2 ml of DBU is added to a suspension of 0.69 g (1.84 mmol) of 5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide and 0.55 g (1.99 mmol) of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine in 5 ml of acetonitrile. The mixture is stirred for 17 h at room temperature and the solvent is then removed by distillation. The residue is taken up in water and washed with diethyl ether. The aqueous phase is acidified with concentrated hydrochloric acid (pH=1) and produces a colorless precipitate, which is filtered off and induced to crystallize by stirring with a little methanol. The resulting product is 0.61 g (60% of theory) of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 144°-145° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:18][C:19](=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:21]=[C:19]([CH3:20])[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(O)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(OCC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 0.5 g of dimethyl 4-hydroxyphenylmalonate, 0.612 g of bromoacetone, 0.616 g of potassium carbonate and 90 ml of dimethylformamide, and then purifying the reaction product by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, the title compound was obtained having an Rf=0.37 (thin layer chromatography over silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([CH:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].C(OCC)(=O)CC(C)=O>>[CH2:1]([CH:4]([CH:10]([OH:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(C)=O)C(=O)OCC
Solvent: CCOC(=O)CC(C)=O
Product: C=CCC(C(=O)OCC)C(C)O
Yield: 60 %

Procedure:
Ethyl 2-allyl-3-hydroxybutyrate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that ethyl 2-allyl-3-oxo-butyrate was used to replace for ethyl acetoacetate. Yield 60%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[C:12]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:15][CH2:14][CH:13]([OH:16])[C:12]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(c2ccc(C(C)(C)C)cc2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=C(c2ccc(C(C)(C)C)cc2)CCC1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
A solution of 25.7 g (0.12 mol) of 3-(4-t-butylphenyl)-2-methyl-2-cyclopenten-1-one (EP 0259977) dissolved in 40 mL of ether was cooled to 0° C. Added dropwise was 43.7 mL (43.7 mmol) of a solution of 1M lithium aluminum hydride in THF. After stirring 20 min, the mixture was quenched by dropwise addition of saturated aqueous NaHSO3. The mixture was dried (MgSO4), solids were filtered and the filtrate was stripped to afford 26.8 g of 1-(4-t-butylphenyl)-2-methyl-cyclopenten-3-ol as an oil which slowly solidified.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C[O-].[Na+].[C:14]([O:18][CH3:19])([CH3:17])(C)C.O>CN(C)C=O>[O:18]1[CH2:19][C@H:14]1[CH2:17][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: COC(C)(C)C
Reactant: Oc1cccc2[nH]ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reaction time: 0.08 h

Procedure:
A 3.2 g portion of 4-hydroxy-1H-indole was dissolved in 31 mL of dimethylformamide in a 50 mL flask equipped with a magnetic stirrer, nitrogen bubbler and thermometer. To it was added 1.27 g of sodium methoxide and the mixture was stirred until a blue-black solution resulted. The warm mixture was placed under vacuum for 5 minutes to remove most of the resulting methanol. To the mixture was added 6 g of oxiranylmethoxysulfonyl-3-nitrobenzene, resulting in an exotherm to about 37° C. The mixture was stirred at ambient temperature for 1 hour, and was then poured into a separatory funnel containing 55 mL of methyl t-butyl ether and 80 mL of water. The mixture was shaken well, and the layers were separated. The organic layer was removed and the aqueous layer was extracted with 2×55 mL of methyl t-butyl ether. The organic layers were combined and back-extracted with 50 mL of 5% aqueous lithium chloride. The layers were separated again, and the organic layer was dried with magnesium sulfate and filtered. The organic filtrate was concentrated under vacuum to about 15 mL of volume, and was seeded with pure desired product and stirred. The product was crystallized to a thick slurry to which 20 mL of heptane was slowly added. The mixture was stirred for one hour more and filtered, and the filter cake was rinsed with 3:1 heptane:methyl t-butyl ether, and then with heptane. The product was dried in a vacuum oven at 40° C. to obtain about 3.5 g of product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([NH:21][C:22](=[O:37])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>>[NH2:8][CH2:9][CH:10]([NH:21][C:22](=[O:37])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=2[N:12]=1
Reactant: Cc1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)NC(CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 60 %

Procedure:
Prepared analogously to Example 17 from rac.-N-[2-tert-butoxycarbonylamino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and trifluoroacetic acid. Yield: 60%; C22H24ClN5O2 (425.92); mass spectrum: (M+H)+=426/428 (chlorine isotope).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1.CCN(CC)CC>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)=[O:1]
Reactant: COC(=O)C1CCCC(CO)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclohexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[C:14](=[O:16])[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Yield: 14 %

Procedure:
A mixture of 1.32 g (6.2 mmol) of 3'-methyl-2-biphenylcarboxylic acid, 40 mL of CH2Cl2 and 0.70 mL (9.6 mmol) of SOCl2 was warmed to reflux for 2 h. The solution was cooled to room temperature and 1.10 mL (9.4 mmol) of SnCl4 was added dropwise with stirring. The dark brown homogenous mixture was stirred for 18 h, poured into 50 mL of cold saturated aqueous NaHCO3, and extracted with 2×50 mL of ether. The ether extracts were combined and washed with 30 mL of saturated NaHCO3 solution, 30 mL of H2 0 and 30 mL of brine, dried (MgSO4) and concentrated in vacuo. Chromatography over SiO2 (Biotage 40 S) using 1% EtOAc in hexanes provided 168 mg (16% yield) of 1-methyl-9-fluorenone (Ladd, D. L. et al., Synthesis and dopaminergic binding of 2-aryldopamine analogues: Phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes. J. Med. Chem. 1986, 29, 1904-1912).
Reaction SMILES: NC(N)=N.NC(N)=S.N[C:10]1[S:11][C:12]([CH2:15][S:16][CH2:17][CH2:18][NH2:19])=[CH:13][N:14]=1.C(ON=O)C>>[NH2:19][CH2:18][CH2:17][S:16][CH2:15][C:12]1[S:11][CH:10]=[N:14][CH:13]=1
Reactant: NCCSCc1cnc(N)s1
Agent: CCON=O
Agent: N=C(N)N
Agent: NC(N)=S
Product: NCCSCc1cncs1

Procedure:
Conversion of the compounds of formula II to the pharmacologically active guanidine and thiourea products is accomplished in a variety of ways. When R2 is --SCH2CH2NH2, the 2-amino group of the 2-amino-5-(2-aminoethyl)thiomethylthiazole is removed, for example by reaction with ethylnitrite, to give the corresponding 5-(2-aminoethyl)thiomethylthiazole compound which is then treated with methyl isothiocyanate to give the corresponding N-methyl-N'-[2-(4-R1 -thiazolylmethylthio)ethyl]thioureas. Reaction of the same 5-(2-aminoethyl)thiomethylthiazole compound with N-cyano-N',S-dimethylisothiourea gives the corresponding N-cyano-N'-methyl-N"-[2-(4-R1 -thiazolylmethylthio)ethyl]guanidines. The guanidine products are also prepared by reaction of the 5-(2-aminoethyl)thiomethylthiazole with dimethyl-N-cyanoimidodithiocarbonate and subsequently reacting the resulting N-cyano-N'-[2-(4-R1 -thiazolylmethylthio)ethyl]-S-methylisothiourea with methylamine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[I:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[I:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:24]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(I)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.70 g, 2.71 mmol), 2-iodo-5-methylbenzoic acid (0.64 g, 2.71 mmol), DIPEA (1.41 mL, 8.13 mmol) and HATU (1.24 g, 3.25 mmol) in DMF (4 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. MS (ESI) 503 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[I:15]N1C(=O)CCC1=O.C(OC(C)C)(C)C>CN(C)C=O>[I:15][C:14]1[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:11][NH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
2.1 g (11 mmol) of 3-(3-nitrophenyl)-1H-pyrazole were dissolved in 25 ml of dry dimethylformamide and 2.63 g (11.7 mmol) of N-iodosuccinimide were added. After 5 hours under stirring at 70° C. the most part of solvent was removed in vacuo and an aqueous solution of sodium thiosulphate was added and the product extracted several times with dichloromethane. The organic phase was then dried over sodium sulphate and evaporated to give, after trituration with diisopropylether, 2.6 g (74%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:8]2[C:17](=[O:18])[C@@:4]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])([C:5]([O:20][CH3:21])=[CH:6][C:7]2=[O:19])[CH2:3]1.[CH3:27][O:28][CH2:29]COC.C(N(C(C)C)CC)(C)C.COCCl>CCCCCC>[CH3:21][O:20][C:5]1[C@:4]2([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:17](=[O:18])[C@@H:8]([C@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[C@@H:2]([O:1][CH2:27][O:28][CH3:29])[CH2:3]2)[C:7](=[O:19])[CH:6]=1
Reactant: COC1=CC(=O)[C@H]2C(=O)[C@]1(CC=C(C)C)C[C@H](O)[C@@]2(C)CCC=C(C)C
Reactant: COCCOC
Agent: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Temperature: 60 °C
Yield: 97 %

Procedure:
A flame-dried round-bottom flask under argon atmosphere is charged with 458 mg (1.22 mmol, 1 equiv.) of starting material 20, 1.3 mL 1,2-dimethoxyethane, and 953 μL (5.34 mmol, 5.5 equiv.) diisopropylethylamine. With stirring, 376 μL (4.95 mmol, 5.1 equiv.) methoxymethyl chloride is added dropwise. The stirring reaction is heated to 60° C. for four hours before being allowed to cool to room temperature. Once the reaction has cooled, it is transferred to a separatory funnel in 50 mL hexane and the organic layer is washed sequentially with 10% aqueous hydrochloric acid, water, and brine. The organic solution is then dried with MgSO4 and concentrated in vacuo to give a clear to yellow oil. The crude product is purified by silica gel chromatography (Rf=0.25 in 4:1 hexane:ethyl acetate) to give 380 mg (97% yield) of 50 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.67 (s, 1H), 5.07 (tt, J=7.1, 1.4 Hz, 1H), 4.97 (tt, J=6.2, 1.3 Hz, 1H), 4.58 (dd, J=36.8, 7.0 Hz, 2H), 3.75 (s, 3H), 3.60 (dd, J=11.2, 5.5 Hz, 1H), 3.32 (s, 3H), 3.18 (s, 3H), 2.48 (dd, J=14.4, 6.2 Hz, 1H), 2.29-2.42 (m, 2H), 2.21 (dd, J=13.4, 5.4 Hz, 3H), 1.87 (ddt, J=18.3, 12.1, 5.5, 5.5 Hz, 3H), 1.78 (dd, J=13.3, 11.4 Hz, 3H), 1.65 (s, 12H), 1.57 (ddd, J=12.9, 4.6 Hz, 1H), 1.27 (ddd, J=12.9, 4.5 Hz, 1H), 0.92 (s, 3H). 13C NMR (126 MHz, CDCl3) δ ppm 205.2, 193.0, 177.3, 134.3, 131.8, 124.3, 119.1, 106.0, 97.1, 77.4, 76.9, 69.2, 57.1, 55.9, 55.8, 46.3, 37.6, 37.4, 29.6, 26.0, 25.9, 21.6, 18.1, 17.8, 16.5. HRMS-ESI (m/z): [M+H]+ calculated for C24H36O5, 405.2636. found 405.2637.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C1C=CC=CC=1>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CCCNc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN(C(=O)c1ccc(F)cc1)c1ccccc1-c1ccccc1
Yield: 84.6 %

Procedure:
Analogously to Example 47b), 10.0 g of ethyl 4-(biphenyl-2-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 50 ml of benzene are reacted with 5.6 g of p-fluorobenzoyl chloride. The reaction product is recrystallized from cyclohexane to obtain 12.1 g (84.6% of theory) of ethyl 4-[p-fluoro-N-(biphenyl-2-yl)-benzamido]butyrate, MP 83° to 84°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:18])[C:5]([C:16]#[N:17])=[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[C:7]=12.IC.[C:21](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[N:3]([CH3:21])[C:4](=[O:18])[C:5]([C:16]#[N:17])=[C:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8](=[O:15])[C:7]=12
Reactant: Cc1[nH]c(=O)c(C#N)c2c1C(=O)c1ccccc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1c2c(c(C#N)c(=O)n1C)-c1ccccc1C2=O

Procedure:
A mixture of 20 parts of 3,9-dihydro-1-methyl-3,9-dioxo-2H-indeno[2,1-c]pyridine-4-carbonitrile, 114 parts of iodomethane, 15 parts of potassium carbonate, and 475 parts of N,N-dimethylformamide is heated at 55°-60° for 2 hours, then diluted with 1500 parts of water. The precipitate which forms is filtered off, dried in air, and crystallized from a mixture of methanol and N,N-dimethylformamide to give 3,9-dihydro-1,2-dimethyl-3,9-dioxo-2H-indeno[2,1-c]-pyridine-4-carbonitrile melting at 271°-273.5°. The product has the formula ##STR13##
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[N:16]1([C:22]2[C:27]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[F:15][C:6]1[C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=[C:4]([CH:5]=1)[CH2:3][NH:2][C:30](=[O:31])[CH:29]=[CH:28][C:27]1[C:22]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)C=Cc1cccnc1N1CCOCC1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2cccnc2N2CCOCC2)cc1F
Yield: 70.1 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (57 mg, 0.22 mmol) was reacted with 3-(2-morpholin-4-yl-pyridin-3-yl)-acrylic acid (52 mg, 1.0 eq) to give N-(5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-morpholin-4-yl-pyridin-3-yl)-acrylamide (67 mg, 69.5%) after purification by column chromatography (Hex/EtOAc=1/7).