Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:34])[CH2:15][C:14]([CH3:36])([CH3:35])[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>C(O)C.O>[NH:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[S:24][C:21]1[O:20][C:19]([CH:18]2[C:17]3[C:16](=[O:34])[CH2:15][C:14]([CH3:36])([CH3:35])[CH2:13][C:12]=3[NH:11][C:10]3=[C:6]([C:4]([OH:5])=[O:3])[NH:7][CH:8]=[C:9]23)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(=O)C2=C(C1)Nc1c(c[nH]c1C(=O)O)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 330 mg (0.657 mmol) of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester in 10 ml ethanol and 1 ml water was added 263 mg of sodium hydroxide in a round bottom flask. The reaction mixture was heated at 40° C. with stirring for 8 hours, and at 30° C. overnight. Water was added to the reaction mixture and it was extracted twice with ethyl acetate. The organic layers were washed with water and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oily residue was dissolved in 1 ml methanol and 14 ml of dichloromethane and purified by chromatography on a prepacked 75 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 98/2 to 92/8 v/v in 50 min; rate: 40 mL/min). The fractions containing the desired product were combined and concentrated to dryness under reduced pressure giving 106 mg of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid (34% yield). Analytical LC/MS method B: [M+H]+=475.5; retention time: 3.01 min; 95% UV purity. 300 MHz 1H NMR (DMSO-d6) δ (ppm): 0.91 (s, 3H); 0.98 (s, 3H); 2.05 (d, J=17.0 Hz, 1H); 2.16 (d, J=17.0 Hz, 1H); 2.50 (d partially masked, J=17.0 Hz, 1H); 2.61 (d, J=17.0 Hz, 1H); 5.14 (s, 1H); 5.97 (d, J=3.5 Hz, 1H); 6.73 (d, J=3.0 Hz, 1H); 6.83 (d, J=3.5 Hz, 1H); de 7.10 à 7.20 (m, 2H); 7.40 (d large, J=8.0 Hz, 1H); 7.52 (d large, J=8.0 Hz, 1H); 8.32 (s large, 1H); 11.3 (s large, 1H); 12.25 (m wide, 1H); 12.3 (s large, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:32])[CH2:20][C:21]([N:23]3[C@H:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][O:25][C:24]3=[O:31])=[O:22])=[C:8]2[CH3:33])=[CH:4][CH:3]=1.[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.CI>C1COCC1>[Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@H:19]([CH3:32])[C@@H:20]([CH3:36])[C:21]([N:23]3[C@H:27]([CH:28]([CH3:29])[CH3:30])[CH2:26][O:25][C:24]3=[O:31])=[O:22])=[C:8]2[CH3:33])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)N1C(=O)OC[C@H]1C(C)C)c(C)n2Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C[C@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1C(C)C)c(C)n2Cc1ccc(Br)cc1
Temperature: -40 °C

Procedure:
To the imide of Example 7, Step 7, isomer A (200 mg, 0.369 mmol) dissolved in THF (2.0 mL) at -78° C. was added a solution of KHMDS (0.5 mL) in toluene (1.10 mL, 0,660 mmol). The temperature was then increased slowly to -40° C. To the mixture recooled at -78° C. was added MeI (100 mL). The temperature was allowed to wam slowly to -40° and the reaction was quenched by the addition of 25% aqueous solution of NH4OAc. The mixture was extracted with EtOAc, dried over Na2SO4, evaporated in vacuo and purified by flash chromatography (20% EtOAc in hexane) to afford the title product (100 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[I:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][C:17](=[O:24])[C:16]2=[CH:25]OC>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH3:11])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:25]=[C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([I:12])[CH:14]=3)[C:19](=[O:23])[NH:18][C:17]2=[O:24])[N:8]=1
Reactant: COc1cnc(CN)nc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: COc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)nc1O
Yield: 34.6 %

Procedure:
2-Aminomethyl-5-methoxy-pyrimidin-4-ol (10 mg, 0.064 mmol) and 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) is stirred at room temperature for 1 hour. The N,N-dimethylformamide is then removed and residue purified to provide the title compound (10 mg, 34%). MS (ESI): 453 (M+1)+1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C.C=C(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:17]1[CH:20]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[Cl:21])[CH2:3][C:4]2([CH3:9])[CH3:5])=[O:11]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1Cl)N2
Temperature: 85 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and 5-bromo-2-chloro-benzaldehyde (13.2 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (6.99 g, 33%) as a light yellow solid: MS (ESI) M+1=422.0.
Reaction SMILES: [CH3:1][N:2](C1CCCCO1)[C:3]1[S:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][N:7]=1>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[S:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][N:7]=1
Reactant: CN(c1ncc(CNc2nccs2)s1)C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CNc1ncc(CNc2nccs2)s1
Yield: 77.3 %

Procedure:
A solution of N-methyl-N-(tetrahydro-2H-pyran-2-yl)-5-((thiazol-2-ylamino)methyl) thiazol-2-amine (50 mg, 0.16 mmol) in 10% TFA in CHCl3 (5 mL) was stirred at RT overnight. After evaporating the solvent, the residue was dissolved in MeOH, neutralized with Na2CO3 and extracted with CHCl3. The organic phase was dried, concentrated and purified by column chromatography yielding N-methyl-5-((thiazol-2-ylamino)methyl)thiazol-2-amine (28 mg, 77%) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:3])[CH3:2])=[C:15]([CH2:20][C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: Oc1ccc(Br)cc1CC(F)(F)F
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)cc1CC(F)(F)F
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
Acetyl chloride (0.91 mL, 12.8 mmol) followed by triethylamine (1.8 mL, 12.8 mmol) were added to a stirred solution of 4-bromo-2-(2,2,2-trifluoroethyl)phenol (2.55 g, 10.7 mmol) dissolved in CH2Cl3 (20 mL). The reaction was stirred for 45 mins and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (2.50 g). LCMS : apci 297 MH+
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:9])[NH:7][CH:8]=1)([CH3:3])[CH3:2].[I:15]N1C(=O)CCC1=O>ClCCl>[I:15][C:8]1[NH:7][C:6]([CH3:9])=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C(C)C)c[nH]c1C
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c(I)c1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 1.03 g of ethyl 4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate in 27 ml of anhydrous dichloromethane was treated with 2.06 g of N-iodosuccinimide and stirred at room temperature for 2 h. The mixture was diluted with a further 50 ml of dichloromethane and washed with 50 ml of saturated sodium thiosulphate solution and 50 ml of saturated sodium hydrogen carbonate solution. The dichloromethane extract was dried over anhydrous sodium sulphate then filtered and evaporated. The residue was triturated with 50 ml of petroleum ether (bp 40-60° C.). The orange solid product was filtered off and dried to give 1.32 g of ethyl 5-iodo-4-isopropyl-2-methyl-1H-pyrrole-3-carboxylate; mass spectrum (ESI) m/z 322 [M+H]+.
Reaction SMILES: I[CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([OH:8])[CH2:4]1.[CH2:9]([NH2:11])[CH3:10]>>[CH2:9]([NH:11][CH2:2][C@@H:3]1[O:7][CH2:6][C@@H:5]([OH:8])[CH2:4]1)[CH3:10]
Reactant: CCN
Reactant: O[C@@H]1CO[C@@H](CI)C1
Product: CCNC[C@H]1C[C@H](O)CO1

Procedure:
A solution of 4.0 g of product from Example 121, Isomer B, and 20 ml of 70%aqueous ethylamine is stirred at room temperature, in a pressure bottle, for 60 hours. The reaction is concentrated in vacuo and the residue purified by chromatography (silica gel: 30% methyl alcohol/chloroform) to give 3.2 g of the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17](=O)[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1(O)[CH:26]=CC=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)Oc1ccccc1

Procedure:
Alternatively, N-t-Butoxycarbonyl-2-phenoxyglycine-n-butyl ester was prepared by heating a mixture of 1.5 g. (0.005 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 0.5 g. (0.005 mol.) of phenol at 150° for 1 hour. The residue was dissolved in ethyl acetate and the resulting solution was washed with cold 10% aqueous sodium hydroxide, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:22](=[O:31])[C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]3=[O:30])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.5 g (20.26 mmol) of tert-butyl(+/−)-2-cyclopentyl-2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-phenyl)acetate were initially charged in 95 ml of dichloromethane, 31.2 ml (405.2 mmol) of trifluoroacetic acid were added and the mixture was stirred at room temperature for 2 h. Water (250 ml) was then added, and the reaction mixture was extracted with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate and concentrated. This gave 6.98 g (95% of theory) of the target compound.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH2:16][CH2:15][C:14]1=[CH:13][C:12](=[O:28])[CH2:11][C@H:10]2[CH3:29].[Cl-].[NH4+]>CS(C)=O>[OH:7][CH2:8][C@@:9]12[C@@H:26]3[C@H:17]([C@H:18]4[C@@:22]([CH2:24][CH2:25]3)([CH3:23])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH2:16][CH:15]=[C:14]1[CH2:13][C:12](=[O:28])[CH2:11][C@H:10]2[CH3:29]
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CC(=O)CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO

Procedure:
To a solution of potassium t-butoxide in dimethylsulfoxide at 25° C. under nitrogen is added with stirring 19-hydroxy-1β-methyl-4-androstene-3,17-dione in dimethylsulfoxide. After 15 minutes the mixture is poured onto a cold aqueous ammonium chloride solution. The solid is rapidly filtered, washed well with water and dissolved in ether. The ether solution is again washed with water and dried over sodium sulfate. The ether is removed at room temperature to yield 19-hydroxy-1β-methyl-5-androstene-3,17-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][NH2:20].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH2:19][CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccn1)c1ccc(Br)cc1
Reaction time: 12 h
Yield: 97.9 %

Procedure:
Add a solution of 4-bromo-benzenesulfonyl chloride (1.278 g, 5.0 mmol) in 10 mL dichloromethane at r.t. to a solution of 2-pyridin-2-yl-ethylamine (611 mg, 5.0 mmol) and triethylamine (708 μL, 5.0 mmol) in 5 mL dichloromethane over a period of 20 min via syringe pump and stir for 12 h. Add 20 mL saturated aqueous sodium bicarbonate solution and extract the aqueous phase with dichloromethane. Wash the combined organic extracts with brine, dry over sodium sulfate, filtrate and concentrate under reduced pressure to obtain 4-bromo-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (1.67 g) as a pale yellow oil which slowly crystallizes upon storage at ambient temperature. Further purification is not necessary. MS (m/e): 342 (M+H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:19]=2)[N:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:19]=2)[N:3]=1
Reactant: COc1ccc(Cn2cc(Cn3nc(I)c4c([N+](=O)[O-])cccc43)cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cc(Cn3nc(I)c4c(N)cccc43)cn2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To 3-iodo-1-((1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)-4-nitro-1H-indazole (1.13 g, 2.31 mmol) in EtOH/H2O (20 mL/5 mL) was added iron (1.29 g, 23.1 mmol) and NH4Cl (0.124 g, 2.31 mmol). The reaction mixture was heated to 80° C. and stirred for 3 hours. The reaction mixture was concentrated, diluted with EtOAc (30 mL) and Et3N (5 mL). The reaction mixture was heated to reflux for 30 minutes and filtered through Celite®, and the filter pad was washed with DCM/MeOH (50 mL, 10:1). The filtrate was concentrated to provide the desired product (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH:12]([N:25]1[CH2:28][CH:27](OS(C)(=O)=O)[CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH:12]([N:25]1[CH2:28][CH:27]([O:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:26]1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Reaction time: 0.17 h

Procedure:
A solution of 3,4 dichlorophenol (4.12 g, 25.3 mmol) in DMF (150 ml) under argon is treated with a 60% dispersion of sodium hydride in mineral oil (40.4 mmol) and the reaction mixture stirred for 10 minutes. A solution of Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (7.27 g, 22.96 mmol) in DMF (50 ml) is added and the reaction mixture left to stir at 60° C. for 20 hours. The reaction mixture is partitioned between ethylacetate and water. The organic phase is washed with water (×2), dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution with 1:4 ethylacetate/isohexane) to afford 1-Benzhydryl-3-(3,4-dichloro-phenoxy)-azetidine. [M+H] 383.8
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([CH2:12][CH3:13])[C:10]#[N:11].[CH2:14](N)[CH2:15][NH2:16]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([C:10]1[NH:16][CH2:15][CH2:14][N:11]=1)[CH2:12][CH3:13]
Reactant: NCCN
Reactant: CCC(C#N)c1cc(F)ccc1F
Product: CCC(C1=NCCN1)c1cc(F)ccc1F

Procedure:
rac-2-[1-(2,5-Difluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,5-difluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 225.0 ((M+H)+.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C1COCC1>[CH:14]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][O:11][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:16])[CH3:15]
Reactant: OCc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1)(C(C)C)C(C)C
Reaction time: 0.08 h

Procedure:
To a solution of (1H-indol-5-yl)-methanol (1.00 g, 6.79 mmol) in THF (60 mL), cooled to 0° C., was added sodium hydride (60% in mineral oil; 1.36 g, 34.0 mmol) portionwise. After stirring for 5 min, triisopropylsilyl chloride (2.88 mL, 13.6 mmol) was added, and the resulting solution was stirred at RT for 2 h. The reaction was quenched by addition of a saturated aqueous NaHCO3 solution at 0° C. The aqueous layer was repeatedly extracted with EtOAc, and the combined organics were washed with H2O (1×) and brine (1×), dried (phase separator) and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane to c-hexane/EtOAc 9:1) afforded the title compound as a white solid. TLC, Rf (c-hexane/EtOAc 9:1)=0.72. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 7.61 (s, 1H), 7.49 (d, 1H), 7.32 (d, 1H), 6.93 (d, 1H), 6.57 (d, 1H), 4.92 (s, 2H), 1.60-1.85 (m, 3H), 1.01-1.12 (m, 39H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>O1CCCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([O:32][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:9]32[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[NH:23][C:22]3=[O:31])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: O=C1CC(c2cc(Br)ccc2OC2CCNCC2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2ccc(Br)cc2C2CC(=O)NC(c3cccc(F)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 4 h

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(4-piperidinyloxy)-phenyl]-6-chloro-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.1 mmol), acetyl chloride (9.4 mg, 0.12 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.027 mL, 0.2 mmol) at r.t. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was triturated in dichloromethane and hexanes to give the title compound as a off white solid (Yield: 43 mg).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[N:8]=[C:9]([C:13]3[C:14]([NH2:18])=[N:15][O:16][N:17]=3)[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH:33][C:34]1[CH:35]=[C:36]([C:40](=[O:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu](I)I>[NH2:18][C:14]1[C:13]([C:9]2[N:10]([CH2:11][CH3:12])[C:4]3[CH:3]=[C:2]([O:33][C:34]4[CH:35]=[C:36]([C:40](=[O:42])[CH3:41])[CH:37]=[CH:38][CH:39]=4)[N:7]=[CH:6][C:5]=3[N:8]=2)=[N:17][O:16][N:15]=1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Br)cc21
Reactant: CC(=O)c1cccc(O)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(C(C)=O)c3)cc21
Temperature: 25 °C
Yield: 55.9 %

Procedure:
Under nitrogen, a suspension of the product from Example 9, Step 2 (42.7 mg, 138 μmol) in toluene (10 mL) was treated with copper iodide (26.3 mg, 138 μmol), 1,10-phenanthroline (45 mg, 245 μmol), 1-(3-hydroxyphenyl)ethanone (28.2 mg, 207 μmol), and cesium carbonate (90 mg, 276 μmol). This mixture was then heated to reflux for 36 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 ml), filtered through a celite pad and then the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (28.1 mg, 43%). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23]([OH:30])[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C(C)C>[N+:27]([C:26]1[CH:21]=[CH:22][C:23]([O:30][C:7]2[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(Oc2ccc([N+](=O)[O-])cc2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 54.5 %

Procedure:
A mixture of 7.0 g (0.022 mol) of product of Example 19, 3.03 g (0.022 mol) of p-nitrophenol and 3.31 g (0.024 mol) of K2CO3 in 75 ml of methyl isobutyl ketone was refluxed for 17 hours. The cooled reaction mixture was concentrated in vacuo. The residue was dissolved in ether, washed with H2O, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized in hot hexane to give 5.09 g of tan solid. The solid was purified by HPLC using 3% ethyl acetate/cyclohexane as eluting solvent affording 3.88 g (41.6%) of product as a white solid; mp 111.5°-113.5° C.