Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:35][C:36](=[O:37])[NH2:38])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
A mixture of the compound obtained in Example 66 (391 mg, 0.80 mmol), 2-bromoacetamide (132 mg, 0.96 mmol), potassium carbonate (265 mg, 1.92 mmol) and DMF (5mL) was stirred at room temperature for 2 days. To the reaction mixture was added water (15 mL), and the mixture was extracted with ethyl acetate (15 mL×3). The organic layer was washed with water (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over, anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (357 mg, 0.65 mmol, Yield 82%) as a colorless oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[N:23]([N:37]=[CH:38][N:39]=4)[C:24]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:36])[NH:31][CH2:30]5)=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[C:10](=[O:40])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[O:40]=[C:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]2[C:22]3[N:23]([N:37]=[CH:38][N:39]=3)[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[NH:31][CH2:30]4)=[CH:25][N:26]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ncnc34)cc2)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2cc(-c3cnc(Nc4ccc(N5CCNCC5=O)cc4)c4ncnn34)ccc21
Yield: 86.3 %

Procedure:
A solution of 3-oxo-4-{4-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (59 mg, 0.1 mmol) in 3:1 DCM:TFA (1.2 mL) is stirred at room temperature for 1 hour. The reaction mixture is diluted with DCM and basified with sat. NaHCO3. The aqueous layer is extracted with DCM (3×) and the organic layers are combined, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a yellow solid (38 mg, 86%). 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.07 (2H, m), 3.44 (2H, s), 3.64 (2H, m), 4.50 (2H, s), 7.32 (2H, d), 7.83 (1H, d), 8.04-8.10 (4H, m), 8.22 (1H, s), 8.70 (1H, br s), 8.74 (1H, s), 10.25 (1H, s). LCMS: Rt 7.17 min (93.7%), m/z (APCI) 441 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[CH:7][N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[CH:7][N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Temperature: 120 °C
Yield: 87 %

Procedure:
A microwave vial containing 3-acetyl-5-methyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.363 g, 1.2 mmol) and N,N-dimethylformamide dimethylacetal (2.5 mL) was heated at 120° C. for 20 min. The crude material was concentrated and purified by flash column chromatography (silica gel; methylene chloride to 1:9 methanol/methylene chloride) to provide 3-[3-(dimethylamino)prop-2-enoyl]-5-methyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.365 g, 87%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]([C:28]1[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[N:29]=[N:30][C:31]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:32][CH:33]=1)=[O:27]
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 132 from 4-chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No.65202-50-8]. MS (m/e)=502.1 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:10](=O)[C:9]2=[O:21])=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>Cl.CO>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:10]3[C:9](=[O:21])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:15]([F:18])([F:17])[F:16])=[N:32]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1C(=O)N(c2ccc(I)cc2)CCC1C(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
1-(4-iodophenyl)-4-(trifluoroacetyl)-2,3-piperidinedione from Part C (10.0 g, 24.3 mmol) and 4-methoxyphenylhydrazine hydrochloride (4.28 g, 24.3 mmol) were dissolved in HCl (1N, 200 mL) and methanol (400 mL). The mixture was refluxed overnight. The reaction mixture was cooled to room temperature and quenched with water. It was extracted with ethyl acetate, washed with brine, and dried (Na2SO4). Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent afforded the desired pyrazole 9.28 g (74%). 1HNMR (CDCl3) δ 7.69 (d, 2H), 7.45 (d, 2H), 7.06 (d, 2H), 6.92 (d, 2H), 4.11 (t, 2H), 3.81 (s, 3H), 3.15 (t, 2H) ppm; Mass Spec (M+H)+514.3.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH:23]=O)[CH2:13]1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:25].[CH2:26]([O:33][C:34]([N:36]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:37][CH3:38])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:25].[CH3:1][N:2]([CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH2:23][N:42]2[CH2:43][CH2:44][CH:39]([N:36]([C:34]([O:33][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:37][CH3:38])[CH2:40][CH2:41]2)[CH2:13]1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C1CC(C=O)C(c2ccccc2)C1)S(=O)(=O)c1ccccc1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCN(C(=O)OCc1ccccc1)C1CCN(CC2CC(N(C)S(=O)(=O)c3ccccc3)CC2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
To a solution of 1-(RS)-(N-(methyl)-N-(phenylsulfonyl)amino)-3-(SR)-(formyl)-4-(SR)-phenylcyclopentane (from Step D, derived from Higher Rf isomer in Step C) (10 mg, 0.029 mmol) (from Step F) in 1,2-dichloroethane (1 mL) was added 4-(N-(benzyloxycarbonyl)-N-(ethyl)amino)piperidine hydrochloride (18 mg, 0.058 mmol) and DIPEA (0.010 mL, 0.058 mmol). After 15 min, sodium triacetoxyborohydride (19 mg, 0.087 mmol) was added and the reaction was stirred at RT for 4-16 h. The reaction was evaporated under nitrogen, quenched with aq. sodium carbonate and extracted 3 times with ethyl acetate. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by Prep TLC eluting with 2-5% methanol in methylene chloride to give the title product (17 mg) as the free amine. The hydrochloride salt was prepared by taking up the free amine in ether, addition of excess 1M hydrogen chloride in ether and evaporation to dryness to afford the title compound usually as a white solid.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][OH:18].[H-].[Na+]>O1CCCC1>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: COc1ccc(CO)cc1OC
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1=C(C)C(OCc2ccc(OC)c(OC)c2)CC1=O
Reaction time: 0.5 h

Procedure:
2-Allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part) was dropwise added to a mixture of 3,4-dimethoxybenzyl alcohol (4 parts), tetrahydrofuran (4 parts) and sodium hydride (1/40 part) in the same flask as used in Example 1 at a temperature of 10° to 20° C. for 30 minutes. Then, the reaction mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the mixture was treated in the same manner as in Example 25 to obtain 2-allyl-3-methyl-4-(3,4-dimethoxybenzyloxy)-2-cyclopentenone. Yield, 96%. nD20 1.5514.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])[CH:7]=[C:8]([NH:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13])[CH:9]=1)(=[O:3])[NH2:2].[OH-].[Na+].O>C(Cl)Cl>[OH2:3].[C:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:17])[C:12]([OH:14])=[O:13])[CH:7]=[C:6]([NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(=O)Nc1cc(NC(=O)C(=O)OCC)cc(C(N)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(NC(=O)C(=O)O)cc(NC(=O)C(=O)O)c1

Procedure:
A mixture of 5.26 gm. (0.015 mole) of diethyl (5-carbamoyl-m-phenylene)dioxamate, 33 ml. of 1N sodium hydroxide solution and 50 ml. of water is stirred for twenty minutes. Methylene chloride (85 ml.) is added and stirring continued for an additional thirty minutes. The aqueous layer is separated and acidified by the addition of dilute hydrochloric acid. The precipitate is removed by filtration and washed with water. The solid is purified by dissolving it in a dilute solution of THAM, filtering the solution and reprecipitation by the addition of a filtered solution of dilute hydrochloric acid. There is obtained 4.7 gm. of material melting at 220° (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:60]>ClCCl.CO>[ClH:60].[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:21][CH:20]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reactant: Cc1ccc(CO)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(COc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cn1
Temperature: 25 °C

Procedure:
A mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (700 mg, 2.74 mmol, Description 3) and (6-methyl-3-pyridinyl)methanol (338 mg, 2.74 mmol) in dichloromethane (30 ml) was stirred under argon at room temperature, Triphenylphosphine (719 mg, 2.74 mmol) and diisopropyl azodicarboxylate (0.533 ml, 2.74 mmol) were then successively added. The resulting mixture was stirred at room temperature under argon for 16 hours. The reaction mixture was washed with water, dried over sodium sulphate, filtered and evaporated. The desired product was purified by SCX column eluting with 1 M ammonia in methanol solution and column chromatography on silica using 1 to 99% ethyl acetate in n-pentane to give a white solid. The free base solid was dissolved in methanol and treated with ethereal hydrochloride to give the title compound (554 mg).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:18])[C:15]=2[O:16][CH3:17])=[C:12]([OH:19])[CH:11]=[C:10]([O:20][CH3:21])[CH:9]=3)=[CH:4][C:3]=1[O:24][CH3:25].[C:26]([O-])(=[O:28])[CH3:27].[Na+].C(OC(=O)C)(=O)C>>[C:26]([O:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:18])[C:15]=2[O:16][CH3:17])=[C:12]([OH:19])[CH:11]=[C:10]([O:20][CH3:21])[CH:9]=3)=[CH:4][C:3]=1[O:24][CH3:25])(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(O)c(OC)c3)oc2c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(OC(C)=O)c(OC)c3)oc2c1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A mixture of 250 mg of 4',5-dihydroxy-3,3',7-trimethoxyflavone, 60 mg of sodium acetate and 70 mg of acetic anhydride was heated at 100° C. for 2 hours. The reaction mixture was evaporated under reduced pressure, and the residue was extracted with 30 ml of chloroform. Removal of the solvent from the extract and subsequent recrystallization of the residue from methanol gave 250 mg (90% yield) of 4'-acetoxy-5-hydroxy-3,3',7-trimethoxyflavone as yellow crystals: m.p. 168°-169° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])(=[O:4])=[O:3].[C:13]([N:15]=[C:16]([NH2:18])[NH2:17])#[N:14].[OH-].[K+]>COCCO.O>[NH2:14][C:13]1[N:15]=[C:16]([NH2:18])[N:17]=[C:8]([C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[N:9]=1
Reactant: N#CN=C(N)N
Reactant: CS(=O)(=O)c1cccc(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CS(=O)(=O)c1cccc(-c2nc(N)nc(N)n2)c1

Procedure:
5.0 g of m-methylsulfonylbenzonitrile (101°-103° C.), 2.8 g of dicyanodiamide and 2.0 g of caustic potash are refluxed in 20 ml of methyl cellosolve for 3 hours. After cooling, the mixture is diluted with water, and the separated crystals are recrystallized from ethanol. Melting point: 228°-289° C.; yield: 4.8 g.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]4)=[C:18]([F:33])[C:11]=3[C:12](=O)[O:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>ClC1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]4)=[C:18]([F:33])[C:11]=3[C:12](=[S:43])[O:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCC1CCC(c2ccc3c(c2F)c(=O)oc2c(F)c(OCCCC)ccc23)CC1
Solvent: Clc1ccccc1
Product: CCCCCC1CCC(c2ccc3c(c2F)c(=S)oc2c(F)c(OCCCC)ccc23)CC1
Yield: 65.3 %

Procedure:
11.7 g (25.6 mmol) of 3-butoxy-4,7-difluoro-8-(4-pentylcyclohexyl)-benzo[c]chromen-6-one and 11.4 g (28.2 mmol) of Lawesson's reagent were refluxed for 16 hours in 130 ml of chlorobenzene. The solution was subsequently filtered through silica gel and evaporated, and the crude product was purified by crystallisation from MTB ether, giving 7.9 g (65%) of 3-butoxy-4,7-difluoro-8-(4-pentylcyclohexyl)benzo[c]chromene-6-thione as yellow crystals.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH:12]=1)=[O:7].[F:31][CH:32]([F:41])[O:33][C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:4][O:5][C:6]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:32]([F:41])[F:31])=[CH:35][CH:36]=3)=[CH:19][CH:20]=2)[CH:12]=1)=[O:7]
Reactant: COC(=O)c1cc(CSc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(CSc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
[1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (12.8 mg) was added to a degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulphanylmethyl]-furan-2-carboxylic acid methyl ester (151) (200 mg, 0.516 mmoles), 1-difluoromethoxy-4-iodo-benzene (153 mg, 0.568 mmoles) and 2M aqueous cesium carbonate (4.12 ml) in 1,4-dioxan (15 ml). The mixture was placed under an argon atmosphere and was heated at 100° C. for 20 hours. After cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water, and the mixture adjusted to pH=2 with 1M aqueous hydrochloric acid. The organic phase was washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography, using heptane/ethyl acetate 9:1v/v as eluent, to afford compound 152(126 mg) as a white solid. LC/MS System A; Rt=4.17 mins.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-])=O.Cl.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>C(#N)C.[Zn]>[NH2:1][CH2:4][CH:5]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCN
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCNC(CN)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 148.3 %

Procedure:
trans-β-Nitrostyrene (4.04 g, 27.1 mmol) was added to a solution of ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol), and N,N-diisopropylethylamine (9.43 mL, 54.2 mmol) in acetonitrile (70 mL). After 15 min, anhydrous hydrochloric acid gas was bubbled into the solution until acidic. The mixture was concentrated, redissolved in ethanol (60 mL) and aqueous hydrochloric acid (12M; 30 mL), and cooled to 0° C. Zinc dust (8.80 g, 134 mmol) was added in portions over 5 min. After 0.5 h, the mixture was concentrated to remove ethanol and saturated aqueous sodium carbonate was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound (9.5 g). MS 237 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])OCC1CO1>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:41][CH:31]([OH:30])[CH2:32][C:33]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(OCC2CO2)cc(OC)c1OC
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Solvent: CC(C)O
Product: COc1cc(CC(O)CN2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)cc(OC)c1OC
Temperature: 70 °C
Yield: 121 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (+/−)-2-(3,4,5-Trimethoxy-phenoxymethyl)-oxirane(95.2 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→100% acetone in hexanes) affording the desired product (145.9 mg) as an oil. ESMS: MH+ 619.4 (base).
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][S:14][CH3:15])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[OH:1][CH:2]([CH2:12][CH2:13][S:14]([CH3:15])=[O:21])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCOC(=O)C(O)CCSC
Solvent: ClCCl
Product: CCCCCCOC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of hexyl 2-hydroxy-4-(methylthio)butanoate (5.03 g, 21.46 mmol) in dichloromethane at 0° C. was added m-chloroperoxybenzoic acid (mCPBA) portionwise over 20 min. The resulting mixture was allowed to warm to room temperature with stirring overnight. The reaction was washed with saturated sodium bicarbonate (3×100 mL), 1N HCl (1×80 mL), and brine (1×80 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give ˜6 g of a crude oil. The oil was purified by silica gel chromatography with 0-6% methanol/dichloromethane to give an oil (4.10 g, 76%). 1H NMR (500 MHz, chloroform-d) δ ppm 0.89 (t, J=6.68 Hz, 3 H) 1.25-1.39 (m, 6 H) 1.67 (quin, J=6.99 Hz, 2 H) 2.05-2.17 (m, 1 H) 2.32-2.42 (m, 1 H) 2.56-2.63 (m, 3 H) 2.72-2.97 (m, 2 H) 3.34-3.44 (m, 1 H) 4.15-4.24 (m, 2 H) 4.26-4.36 (m, 1 H). m/z 251 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28]OS(C)(=O)=O)[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[C-:43]#[N:44].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][C:43]#[N:44])[CH:25]=[C:24]([Br:34])[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: [C-]#N
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(COS(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CC#N)c2)c1CCC(=O)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-methanesulfonyloxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (2.51 g, 3.74 mmol) in DMF (40 mL), KCN (292 mg, 4.48 mmol) was added and stirred a 60° C. overnight. The reaction was diluted with EtOAc (250 mL) washed with water (100 mL×2), brine (50 mL), dried with Na2SO4. Concentration under reduced pressure provided an oil. Flash column chromatography (30% EtOAc/Hex) provided a light yellow oil (1.19 g, 53% yield). 1H NMR (CDCl3): δ 7.08 (t, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H), 6.77 (d, 1H), 6.68 (d, 1H), 4.17-4.06 (m, 4H), 4.01-3.91 (m, 4H), 3.68 (s, 2H), 2.97 (dd, 2H), 2.63 (dd, 2H), 2.56-2.46 (m, 4H), 2.17-0.89 (m, 16H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>C(O)(=O)C>[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Cl
Reactant: Nc1ccccc1Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Nc1ccccc1Br

Procedure:
The title compound is prepared in analogy to Example 19d, starting from 0.5 g (1.756 mmol) 4-chloro-3-nitro-6-phenyl-quinoline (Example 53d) and 0.339 g (1.932 mmol) 2-bromoaniline in 3 ml acetic acid. mp: 198-204° C.; MS: 420 (M++1); HPLC: tret=12.17 min (Grad 1).