Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=O)[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]2.[Cl-].[NH4+].[CH3:21][C:22]([CH3:24])=O>[Zn]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=[C:22]([CH3:24])[CH3:21])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]2
Reactant: Cc1ccc2c(c1)CC(c1ccccc1)N2N=O
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)=NN1c2ccc(C)cc2CC1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methyl-1-nitroso-2-phenylindoline (0.8 g, 0.00336 mol) was dissolved in acetone (30 mL), and to this saturated ammonium chloride solution (4.4 mL) was added. The reaction mixture was cooled to 0° C., and zinc dust (1.31 g, 0.0201 mol) was added portionwise over 30 min. at 0° C. The reaction was stirred for 1 h at RT, and after completion of reaction (monitored by TLC), the solvent was removed under reduced pressure. Water (100 mL) was added and the mixture extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product as a yellow colored oil (0.6 g).
Reaction SMILES: [C:1]([O:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]#[N:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:17]([C:13]1[C:14]([O:16][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)#[N:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1OC(=O)c1ccccc1
Yield: 80.9 %

Procedure:
The general procedure of Example 90 was followed using 1.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine and 0.58 g of benzoyl chloride, thereby producing 1.15 g of the title compound in a yield of 80%.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[O:4][C:5]1([CH2:13][OH:14])[CH2:10][CH2:9][CH2:8][N:7]([N:11]=O)[CH2:6]1>C(O)(=O)C.O.[Zn]>[NH2:11][N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH2:13][OH:14])([O:4][C:3]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:2]=2[F:1])[CH2:6]1
Reactant: O=NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Temperature: 25 °C

Procedure:
To the suspension of zinc dust (10 mmol, 0.65 g) in a mixture of acetic acid (5 mL) and water (5 mL) was added a solution of (3-(2,5-difluorophenoxy)-1-nitrosopiperidin-3-yl)methanol in acetic acid. The reaction mixture was stirred at room temperature for an hour. The mixture was filtered. The filtrate was basified with sodium hydroxide aqueous solution. The organics were extracted with EtOAc. The product, (1-amino-3-(2,5-difluorophenoxy)piperidin-3-yl)methanol, was obtained after removal of the solvent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:3]=1.[NH:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:19]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[N:3]=2)[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH2:21][CH2:20]1
Reactant: Fc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: c1cc2c(cn1)CCN2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(N2CCc3cnccc32)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-(2-fluoro-phenyl)-quinazoline from Step C example 1 (0.04 g, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) and to it was added 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (0.02 g, 0.16 mmol) followed by cesium carbonate (0.12 g, 0.36 mmol). The mixture was magnetically stirred at room temperature for 0.5 hr. The solvent was removed and title compound was obtained pure after column purification on a HPLC reverse phase column, using a water and acetonitile gradient containing 0.1% trifluoroacetic acid to yield (0.01 g, 19%). MS (ES) 343.0 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=3)[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2cc(-c3ccc(OC(F)(F)F)cc3)nc(-c3ccccc3)n2)cc1

Procedure:
The title compound was prepared by reacting (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.15 g, 0.41 mmol) with 4-trifluoromethoxy-phenyl boronic acid (0.09 g, 4.3 mmol) in presence of (PPh3)4Pd (0.02 g, 0.017 mmol) and 2 M sodium carbonate (0.35 g in 1.5 mL H2O) in DMF at 80° C. for 12 hours. Followed by work up and column purification to yield the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:23][PH:24]([O-])([O-:28])[O:25][CH2:26][CH3:27].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:24]([CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 68 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 19-b, (10 g, 0.026 mol), ethyl methylphosphite (5.6 g, 0.052 mol) and Et3N (7.88 g, 0.78 mol) in THF (100 ml) was added PdCl2(dppf) (2.2 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the product, 19-c, (6.9 g, 68%).
Reaction SMILES: [K+].[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.CI.[CH3:18]N(C)C=O>O>[CH3:18][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=1
Reactant: O=C([O-])C(=O)C=Cc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)C(=O)C=Cc1cccc(Br)c1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
4-(3-Bromo-phenyl)-2-oxo-3-butenoic acid potassium salt (41.0 g, 140.0 mmol) prepared in Step 1 and methyl iodide (15.0 mL, 238.0 mmol) were added to N,N-dimethylformamide (200.0 mL). The reaction mixture was stirred at 75° C. for 4 hours and then distilled water was added thereto. The reaction mixture was extracted with ethyl acetate. The extract was washed with 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=1/8) to give 10.0 g of the titled compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (100 mg, 0.21 mmol) and 2-furanylboronic acid (50 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E112). MS (ES+) m/e 460 [M+H]+.
Reaction SMILES: Cl[C:2](=[N:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23].CN(C)C1C=CC=CC=1.Cl>ClCCl>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[N:23]([C:22]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:21]=2[CH3:20])[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:9][N:10]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1ccccc1C(Cl)=NN=C(Cl)c1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1-c1c(C)cccc1C
Temperature: 120 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
Then, 12.6 g (43.3 mmol) of [chloro(2-methylphenyl)methanone][chloro(phenyl)methylidene]hydrazone obtained in Step 2, 15.7 g (134.5 mmol) of 2,6-dimethylaniline, and 100 ml of N,N-dimethylaniline were put into a 500-ml recovery flask and heated and stirred at 120° C. for 20 hours. After reaction for the predetermined time, this reacted solution was slowly added to 200 ml of 1N hydrochloric acid. Dichloromethane was added to this solution and an objective substance was extracted to an organic layer. The obtained organic layer was washed with water and an aqueous solution of sodium hydrogen carbonate, and was dried over magnesium sulfate. The magnesium sulfate was removed by gravity filtration, and the obtained filtrate was concentrated to give a black liquid. This liquid was purified by silica gel column chromatography. A mixed solvent of ethyl acetate and hexane in a ratio of 1:5 was used as a developing solvent. The obtained fraction was concentrated to give a white solid. This solid was recrystallized with ethyl acetate to give 4.5 g of a white solid of Hmpptz-dmp in a yield of 31%. Synthesis Scheme (a-3) of Step 3 is shown below.
Reaction SMILES: [CH2:1]([S:4][C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=[C:8](N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH2:3].Cl.C([OH:25])C>>[CH2:1]([S:4][C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=[C:8]([OH:25])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH2:3]
Reactant: CCO
Reactant: C=CCSC(=CC=C(C(=O)OCC)N(C)C)C(=O)OCC
Agent: Cl
Product: C=CCSC(=CC=C(O)C(=O)OCC)C(=O)OCC
Temperature: 20 °C
Reaction time: 0.05 h

Procedure:
The procedure is as in Example 2, starting with diethyl 5-allylthio-2-dimethylamino-2,4-hexadienedioate (5.1 g) and 1N aqueous hydrochloric acid solution (24.4 cc) in ethanol (24.4 cc). The mixture is heated to boiling for 3 minutes, and then cooled to a temperature in the region of 20° C. After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (75:25 by volume) as eluent, diethyl 5-allylthio-2-hydroxy-2,4-hexadienedioate (2.3 g) is obtained in the form of a yellow oil [Rf=0.2; thin layer chromatography on silica gel; eluent: cyclohexane/ethyl acetate (75:25 by volume)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([Cl:21])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
5.00 g (19.18 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were dissolved in 36.51 g (306.84 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for four hours and then concentrated under reduced pressure. Drying under fine vacuum gave 5.4 g (100% of theory) of the title compound as a brownish oil.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12]N1C(=O)CCC1=O.OS(O)(=O)=O>C(O)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([I:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 88 h

Procedure:
To a stirred slurry of methyl 2-iodo-benzoate (5.0 g, 0.019 mol) and N-bromosuccinimide (3.74 g, 0.021 mol) in acetic acid (10 mL) was added concentrated H2SO4 (10 mL) dropwise, keeping the temperature at 20-40° C. The mixture was stirred at room temperature for 88 hours and then heated at 50° C. for 4 hours. The mixture was cooled to 10° C., treated with 40 g of ice water, and extracted with 50 mL of CH2Cl2. The organic phase was washed in succession with 2×50 mL 5% NaHCO3, 50 mL 10% Na2S2O3, 50 mL water, and concentrated to colorless oil. The residue was purified by column chromatography (silica gel, 10:90 EtOAc:hexane) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J=4 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.27 (dd, J=8, 4 Hz, 1H), 3.92 (s, 3H); MS (DCl/NH3) [M+NH4]+ at 358, [M+NH3.NH4]+ at 375.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)S(O[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][C@H:22]([N:29]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][O:24]2)(=O)=O>>[CH2:37]([N:29]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:22]1[CH2:21][C:20]2[C:25](=[CH:26][CH:27]=[CH:28][C:19]=2[C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[O:24][CH2:23]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Reactant: COc1ncc(B(O)O)cc1F
Product: COc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cc1F
Yield: 71 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 71% yield, starting from 5-fluoro-6-methoxypyridin-3-ylboronic acid (1.7 equiv) and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (1 equiv): 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, 1 H), 7.73 (dd, 1 H), 7.23-7.37 (m, 8 H), 7.06-7.22 (m, 3 H), 6.78 (dd, 2 H), 4.34 (d, 1 H), 3.92-4.08 (m, 4 H), 3.60-3.79 (m, 4 H), 3.18-3.30 (m, 1 H), 2.89-3.10 (m, 2 H); MS (ESI) m/z 455[M+H+].
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[S:29][C:28]([C:30]3[S:31][C:32]([C:35]4[N:36]=[C:37]([C@@H:40]5[CH2:44][CH2:43][CH2:42][N:41]5C(OC(C)(C)C)=O)[NH:38][CH:39]=4)=[CH:33][N:34]=3)=[N:27][CH:26]=2)=[CH:23][N:24]=1)=O)(C)(C)C>ClCCl>[NH:41]1[CH2:42][CH2:43][CH2:44][C@H:40]1[C:37]1[NH:38][CH:39]=[C:35]([C:32]2[S:31][C:30]([C:28]3[S:29][C:25]([C:22]4[N:21]=[C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)[NH:24][CH:23]=4)=[CH:26][N:27]=3)=[N:34][CH:33]=2)[N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cnc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)s3)s2)c[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1[nH]c([C@@H]2CCCN2)nc1-c1cnc(-c2ncc(-c3c[nH]c([C@@H]4CCCN4)n3)s2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
TFA (1.0 mL, 13 mmol) was added to a stirred solution of tert-butyl (2S)-2-(4-(5′-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-2,2′-bi-1,3-thiazol-5-yl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate (55 mg, 0.086 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under vacuum and the crude product was purified by preparative HPLC (Waters Sunfire C18 column 30×150 mm 5 u, eluted with a gradient of 10 to 100% acetonitrile/water/0.1% TFA). Fractions containing the desired product were filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and the compound was released from the cartridge by washing the column with a 2M ammonia in methanol solution. The filtrate was evaporated under reduced pressure to yield 5,5′-bis(2-((2S)-2-pyrrolidinyl)-1H-imidazol-4-yl)-2,2′-bi-1,3-thiazole (39 mg, 0.085 mmol, 99% yield) as an orange solid.
Reaction SMILES: O=O.C1(S)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([O:37][C@H:38]1[C@:45]([CH3:47])([OH:46])[C@@H:44]2[CH2:48][C@@H:40]([C@@:41]([CH3:57])([CH2:49][S:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:42][O:43]2)[CH2:39]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCCCCC.C1C=CC=CC=1.CCCCCC>[C:29]([O:37][C@H:38]1[C@@:45]([CH3:47])([OH:46])[C@@H:44]2[CH2:48][C@@H:40]([C@:41]([CH3:57])([CH2:49][S:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:42][O:43]2)[CH2:39]1)(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@@]1(O)[C@@H]2C[C@H](C[C@H]1OC(=O)c1ccccc1)[C@@](C)(CSc1ccccc1)OO2
Agent: O=O
Agent: Sc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C[C@]1(O)[C@@H]2C[C@H](C[C@H]1OC(=O)c1ccccc1)[C@](C)(CSc1ccccc1)OO2
Temperature: 4 °C
Reaction time: 14 h
Yield: 6 %

Procedure:
Oxygen was bubbled through a solution of the α-benzoate 3b (690 mg, 2.70 mmol) and DBPO (8.5 mg, 0.036 mmol) in hexane-benzene (50 mL, 7:3) with simultaneous addition (syringe pump) of a solution of PhSH (99 mg, 2.0 mmol) in hexane (20 mL) during 10 h. After completion of the thiol addition, the mixture was kept under oxygen for an additional 14 h, cooled to 4° C., and Ph3P (236 mg, 0.90 mmol) was added. The reaction mixture was stirred for 2 h at 5° C. and at rt for additional 1 h. The solvents were then evaporated, and flash chromatography (hexane-EtOAc, 9:1→1:1) afforded a mixture of diastereomeric (1S,4S,5S,7R,8S)-7-benzoyloxy-4,8-dimethyl-4-phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 6a and (1S,4R,5S,7R,8R)-7-benzoyloxy-4,8-dimethyl-4-phenylthiomethyl-2,3-dioxabicyclo[3.3.1]nonan-8-ol 6b (24 mg of ca. 94% purity, 6% yield, 6a/6b ca. 65:35), Rf 0.42 (EtOAc-heaxane, 35:65) as a pale yellow oil. 1H NMR (400 ) MHz, CDCl3, δ): 1.23 (br. s, Me11, 6a), 1.59 (br. s, Me11, 6b), total 3 H; 1.41 (s, Me10, 6b), 1.42 (s, Me10, 6a), total 3 H; 1.91-2.37 (m, total 5 H, H35 +Ha,e6 +Ha,e9, 6a+6b); 3.00 (d, 2J=12.1 Hz, H12, 6b), 3.14 (br. d, 2J=12.1 Hz, H'12, 6b), 3.39 (d, 2J=12.8 Hz, H12, 6a), 3.80 (br. d, 2J=12.8 Hz, H'12, 6a), total 2 H; 3.82 (m, He1, 6a), 3.88 (dd, 3J1e9e =4.1 Hz, 3J1e9a =1.5 Hz, He1, 6b), total 1 H; 5.26 (dd, 1 H, 3J7e6e =5.0 Hz, 3J7e6a =1.7 Hz, He7, 6b), 5.27 (dd, 1 H, 1J7e6e =5.0 Hz, 3J7e6a =1.5 Hz, He7, 6a), total 1 H; 7.09 (m, 1 H), 7.22 (m, 6 b), 7.29 (m, 6a), total 2 H; 7.41-7.47 (m,), 7.54-7.58 (m,), total 5 H; 8.13 (m, 2 H), 13C NMR (100 MHz, CDCl3, δ): Isomer 6a: 22.30 (Me11), 23.42 (C9H2), 23.47 (Me10), 28.81 (C6H2), 29.36 (C5H), 40.78 (C12H2), 73.83 (C8), 74.36 (C7H), 80.85 (C1H), 82.74 (C4), 126.36 (C16H), 128.48 (2CH), 129.00 (2CH), 129.81 (2CH), 129.90 (2CH), 130.15 (C1-benz.), 133.11 (Cp-benz. H), 136.71 (C13), 166.33 (C=O); Isomer 6b: 21.68 (Me11), 23.35 (Me10), 23.56 (C9H2), 28.68 (C6H2), 30.86 (C5H), 40.37 (C12H2), 73.68 (C8), 74.51 (C7H), 81.38 (C1H), 82,83 (C4), 126.12 (C16H), 128.52 (2CH), 128.88 (2CH), 129.06 (2CH), 129.81 (C1-benz.), 129.90 (2CH), 133.18 (Cp-benz. H), 136.25 (C13), 166.25 (C=O).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C1C=CC=CC=1>[CH:13]1[C:14]2[CH:2]([O:1][C:22](=[O:25])[CH:23]=[CH2:24])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: C=CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1c2ccccc2-c2ccccc21
Temperature: 8 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a 250 mL round-bottomed flask was added 9-hydroxyfluorene (5 g, 27.4 mmol) and triethylamine (3.86 ml, 27.4 mmol) in benzene (150 mL) to give a colorless solution. The solution was cooled to 8° C. with an ice bath. Next, acryloyl chloride (2.229 mL, 27.4 mmol) was dissolved in 25 mL of benzene, placed in a dropping funnel, and added over 1 hour with vigorous stirring. The reaction formed a white precipitate. The ice bath was removed and the viscous sludge was stirred overnight at room temperature. The resulting cloudy white suspension was washed with 50 mL water, followed by 50 mL 5% NaOH solution, and 50 mL water. The benzene layer was collected and dried with MgSO4, filtered, and rotovapped to give the 9-fluorenylacrylate as a viscous beige oil which crystallized on cooling to 4° C. (4.73 g, 20.02 mmol, 73.0% yield).
Reaction SMILES: Cl[O-].[Na+].Cl.[CH2:5]([O:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:14]=1[C:15]1[C:16]([CH2:39][O:40][CH3:41])=[C:17]([CH:36]=[N:37][OH:38])[N:18]=[CH:19][C:20]=1[N:21]2S(C1C=CC(C)=CC=1)(=O)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:42][O:43][CH2:44][C:45]#[CH:46]>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:14]=1[C:15]1[C:16]([CH2:39][O:40][CH3:41])=[C:17]([C:36]3[CH:46]=[C:45]([CH2:44][O:43][CH3:42])[O:38][N:37]=3)[N:18]=[CH:19][C:20]=1[NH:21]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCOC
Reactant: COCc1c(C=NO)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: COCc1cc(-c2ncc3[nH]c4cccc(OCc5ccccc5)c4c3c2COC)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature under a protective gas, 1.4 ml of sodium hypochlorite solution is added dropwise to 155 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carbaldehyde oxime hydrochloride in 6 ml of absolute tetrahydrofuran. The mixture is stirred until the oxime has disappeared (TLC control) for one hour at room temperature, then 210 mg of methylpropargyl ether is added dropwise and the mixture is agitated overnight at room temperature. After the solvent has been removed by distillation, the mixture is distributed in ethyl acetate/water, and the organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is dissolved in 8 ml of methanol, combined with 54 mg of sodium methylate, and heated to reflux for one hour. After concentration and distribution in ethyl acetate/concentrated sodium chloride solution, the organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with toluene+ethyl acetate in a ratio of 1:1. The corresponding fractions are combined and crystallized from ethyl acetate, thus obtaining 70 mg, melting point 133°-135° C. (ethyl acetate).