Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][C:8]2=[O:13].C[Si]([C:24]#[N:25])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C.O.C(#N)C>[NH2:25][CH2:24][C:8]1([OH:13])[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1
Reactant: COc1cccc2c1CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: COc1cccc2c1CC(c1ccccc1)CC2(O)CN
Yield: 94.1 %

Procedure:
5-Methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone (1.9 g, 7.5 mmol), the product of Example 1, 3 mL of acetonitrile, 1.9 g (19 mmol) of trimethylsilylcyanide, commercially available from Aldrich Chemical Company, and 100 mg of aluminum chloride were mixed together and heated at reflux temperature for 2 h. The reaction mixture was cooled and concentrated. The residue was dissolved in 6 mL of diethyl ether and the ether solution was added dropwise to a solution of 0.62 g (16 mmol) of lithium aluminum hydride in 14 mL of diethyl ether. After the reaction mixture was heated at reflux temperature for 2 h, 0.6 mL of water was added dropwise, followed by 0.6 mL of 15% aqueous sodium hydroxide solution, followed by 1.8 mL of water. The reaction mixture was stirred until a granular precipitate formed. The solid was filtered and washed with 3×20 mL of methylene chloride. The filtrate was concentrated to give 2.0 g (95% yield) of the title compound as an oil; 1H NMR (d6-DMSO) δ 1.90 (t, 1H), 2.25 (dt, 1H), 2.65-2.85 (m, 2H), 2.95-3.25 (m, 3H), 3.78 (s, 3H), 6.85-7.05 (m, 3H), 7.2-7.5 (m, 5H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][N:30]=3)[C:24]([CH3:38])([CH3:37])[C:23]2=[O:39])[CH2:17][CH2:16]1)=O)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH4+:52].[OH-]>ClCCl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH:25]2[CH2:26][N:22]([CH:18]3[CH2:19][CH2:20][CH2:21][N:15]([C:13]([NH2:52])=[O:12])[CH2:16][CH2:17]3)[C:23](=[O:39])[C:24]2([CH3:38])[CH3:37])=[N:30][CH:31]=1)#[N:36]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCC(N2CC(COc3ccc(C#N)cn3)C(C)(C)C2=O)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2CCCN(C(N)=O)CC2)CC1COc1ccc(C#N)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.75 mL) was added to a solution of Example 2F (0.108 g, 0.24 mmoles) in dichloromethane (0.75 mL) and stirred for one hour. The solvent was evaporated in vacuo. The residue was taken in dichloromethane (1.5 mL) and cooled to −78° C. Triphosgene (24 mg, 0.08 mmoles) was added and stirred for one hour. To the reaction, NH4OH (1 mL) was added and stirred at room temperature for one hour. The product was extracted with dichloromethane, dried with MgSO4, filtered, and evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.48 (dd, J=2.33, 0.64 Hz, 1H), 7.80 (dd, J=8.66, 2.33 Hz, 1H), 6.82 (dd, J=8.66, 0.78 Hz, 1H), 5.81 (b,r, 2H), 4.50 (dd, J=10.87, 6.04 Hz, 1H), 4.36 (dd, J=10.86, 8.24 Hz, 1H), 4.03-4.19 (m, 1H), 3.16 (m, 4H), 3.46 (dd, J=9.85, 7.64 Hz, 1H), 3.08 (dd, J=9.87, 7.94 Hz, 1H), 2.45 (qd, J=7.94, 6.01 Hz, 1H), 1.43-1.82 (m, 6H), 1.24 (s, 3H), 1.06 (s, 3H). MS (APCI+) m/z 386.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:20]2[C:3](=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH:6]([C:14]([O-])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]1[CH2:22][O:21][C:20]2[C:3](=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH:6]([CH2:14][OH:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2c1OCCO2)C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(CO)Cc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
761 mg of tert-butyl (2,3-ethylenedioxybenzyl)malonate was dissolved in 20 ml of ethanol. Then, 0.57 g of sodium borohydride was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with 150 ml of ethyl acetate and washed with 100 ml of water and then with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain 241 mg (yield: 36%) of the desired product as syrup.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=1>C(#N)C>[Br:8][C:15]1[C:10]([Cl:9])=[CH:11][C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])=[N:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
NBS (8.37 g. 47.0 mmol) was added to a solution of N-(4-chloropyridin-2-yl)pivalamide (2.00 g, 9.40 mmol) in dry acetonitrile (20 mL). The resulting suspension was heated for 3 hr and then cooled to r.t. The solvent was removed in vacuo and the crude mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with aqueous NaOH (10%, 2×40 mL), water (40 mL) and dried (MgSO4). The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate and hexane (1/9), to give the title compound as a colourless solid (1.82 g, 66%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26]>O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCCCn1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCCn1ccnc1
Temperature: 90 °C

Procedure:
A mixture of 250.4 g (2 mol) of 3-imidazol-1-ylpropylamine and 82.8 g (0.6 mol) of potassium carbonate in 280 ml of water was heated to 90° C. 155.1 g (1 mol) of 1-fluoro-2-methyl-4-nitrobenzene were added dropwise over 30 minutes and the mixture was maintained at a temperature of 90-95° C. for 4 hours.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[C:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH:14]([C:5]1[C:6](=[O:13])[NH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([O:1][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH:11]=[CH:10][C:9]=2[CH3:12])([CH3:16])[CH3:15]
Reactant: Cc1ccc(O)c2cc(C(C)C)c(=O)[nH]c12
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Temperature: 70 °C
Reaction time: 7 h
Yield: 93.8 %

Procedure:
5-HYdroxy-3-isopropyl-8-methylcarbostyril (1.50 g, 6.91 mmol) was dissolved in dimethylformamide (30 ml). To the solution, potassium carbonate (3.00 g, 21.7 mmol) and prenyl bromide (0.90 ml, 7.67 mmol) were added, and the mixture was stirred at 70° C. for 7 hours. The reaction mixture was condensed under reduced pressure, and the resultant residue was extracted from chloroform-water. The organic phase was washed with saturated aqueous NaCl solution, dried, and condensed under reduced pressure. The residue was recrystallized from chloroform-ethyl acetate to obtain 1.85 g of the title compound as pale yellow needles (97.9%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:37])[CH2:16][CH2:17][C:18](=[O:36])[C@@H:19]([NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C1C=CC=CC=1.C(N[C@@H](CC1C=CC=CC=1)C(=O)CCC(O)=O)(=O)C1C=CC=CC=1.COC(=O)[C@H](CC1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[NH:71]C=1)N.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:8][C:9](=[O:38])[C@H:10]([CH2:14][C:13]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[NH:71][CH:12]=1)[NH:11][C:15](=[O:37])[CH2:16][CH2:17][C:18](=[O:36])[C@@H:19]([NH:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Yield: 90 %

Procedure:
The experimental procedure employed for the synthesis of (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline benzyl ester was followed using the free acid compound 4 (200 mg, 0.6109 mmol, 1.0 eq.), L-tryptophan methyl ester (133 mg, 0.6109 mmol, 1.0 eq.), 1-Hydroxybenzotriazole hydrate (HOBt) (83 mg, 0.6109 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (117 mg, 0.6109 mmol, 1.0 eq.), iPr2NEt (0.11 mL, 0.6110 mmol, 1.0 eq.) and dry DMF/CH2Cl2 (2:8 ratio)(10 mL). Work-up as usual and column chromatography on silica gel elution with 100% EtOAc afforded the (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-tryptophan methyl ester as a yellow solid (0.290 g, 90%); mp 88-90° C.; Rf 0.50 (EtOAc); IR (KBr) ν 1760 (CO), 3230 (NH) cm−1; 1H NMR (300 MHz, CDCl3) δH 2.44 (2H, m, —CH2CO), 2.82 (2H, m, —CH2CO), 3.06 (1H, m, —CHαPh), 3.28 (3H, m, —CHβPh and —CH2Trp), 3.67 (3H, s, —OMe), 4.90 (1H, m, —CH—), 4.99 (1H, m, —CH—), 6.17 (1H, dd, J=2.7 and 7.5 Hz, —NH), 6.88 (1H, d, J=6.9 Hz, —NH), 7.00 (1H, dd, J=2.8 and 6.4 Hz, Trp-H-5′), 7.02-7.56 (12H, m, Ar—H), 7.68 (1H, d, J=1.8 Hz, Trp-H-2′), 7.71 (1H, d, J=1.8 Hz, Ar—H) and 8.27 (1H, br-s, —NH); 13C NMR (75 MHz, CDCl3) δC 27.6, 29.7, 35.0, 35.1, 36.8, 36.9, 52.3, 53.0, 59.4, 59.6, 109.9, 111.3, 118.5, 119.7, 122.2, 123.0, 127.0, 127.6 (2C), 128.5, 128.6 (2C), 129.3, 131.8, 133.8, 136.1, 136.2, 167.1, 171.1, 172.3 and 207.5; HRMS m/z calcd for C31H31N3O5 (M+) 525.22637, found 525.22637.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)=[N:9][C:5]2=[N:6][C:7]=1I.[Li+].[OH-].N#N.[CH3:26][C:27]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:30][S:29](=[O:32])(=[O:31])[CH2:28]1>O1CCOCC1.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].C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:12][C@@H:13]3[CH2:14][O:15][C@@H:16]4[C@H:20]([OH:21])[CH2:19][O:18][C@H:17]34)=[N:9][C:5]2=[N:6][C:7]=1[C:36]1[CH:35]=[CH:34][C:33]([C:27]2([CH3:26])[CH2:28][S:29](=[O:32])(=[O:31])[CH2:30]2)=[CH:38][CH:37]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(I)c(Cl)cc2[nH]1
Reactant: CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CS(=O)(=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1(c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)CS(=O)(=O)C1
Temperature: 80 °C

Procedure:
Step E A solution of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (100 mg, 0.236 mmol), LiOH (29.7 mg, 0.708 mmol), and PdCl2(dppf)-CH2Cl2 adduct (38.6 mg, 0.047 mmol), in a thick-walled tube, was flushed with N2. Then water (0.5 ml) was added, followed by a solution of 3-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thietane 1,1-dioxide (114 mg, from Step D) in dioxane (3.5 ml). The tube was flushed with N2, and placed in a preheated 72° C. hot oil bath and heated to 80° C. for 3 hours. The reaction mixture was cooled to RT and diluted with EtOAc (30 ml) and water (20 ml). The aqueous layer was separated, and extracted with EtOAc (25 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting crude material was purified by Isco™ system, 24 g gold cartridge, 30 ml flow rate, gradient —40/60 (1 min) to 100/0 (15 min) to 100/0 (19 min total run time) of EtOAc/hexanes. The fractions containing product were combined and concentrated to obtain the title compound as an off-white solid. LC-MS: observed m/e: 492.37 (M+H)+ (Rt 0.85/2 min)
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:18]=[C:17]2[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]2=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:21]1[C:16]2[C:17](=[N:18][C:13](/[CH:12]=[CH:11]/[CH2:10][CH2:9][OH:8])=[CH:14][CH:15]=2)[N:19]([CH3:28])[C:20]1=[O:27]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(/C=C/CCO)nc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-[(1E)-4-{[tert-Butyl(dimethyl)silyl]oxy}but-1-en-1-yl]-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-2, 207 mg, 0.51 mmol, 1.0 equiv) was added to anhydrous methanol (5.1 mL) and cooled to 0° C. p-Toluenesulfonic acid (9.7 mg, 0.05 mmol, 0.1 equiv) was added and the resulting solution was stirred at 0° C. for 18 h. Following this duration, LCMS showed complete consumption of 32-2. The contents were diluted ethyl acetate (15 mL) and saturated NaHCO3 (15 mL) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×15 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow oil. Purification by reverse-phase HPLC (10-100% 0.1% TFA in H2O:CH3CN) afforded 32-3 as a colorless oil. MS m/z (M+H): calculated=290.1863; observed=290.1864.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[N+:12](=[CH2:14])=[N-:13].N(NC(N)=O)=O>CCOCC>[N+:12](=[CH:14][C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4]1)=[O:9])=[N-:13]
Reactant: C=[N+]=[N-]
Reactant: CC1(C)CCC(C(=O)Cl)CC1
Agent: NC(=O)NN=O
Solvent: CCOCC
Product: CC1(C)CCC(C(=O)C=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Next at room temperature, 2.0 g of the 4,4-dimethylcyclohexylcarbonyl chloride obtained as above was added dropwise to 100 ml of an ether solution of diazomethane prepared from 10 g of nitrosourea, and the mixture was thereafter stirred at room temperature for about 1 hour. The solvent was distilled off from the reaction mixture in a vacuum, quantitatively giving pale yellow oily 1-diazo-2-(4,4-dimethyl-cyclohexyl)-2-ethanone (Compound I).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([CH:19]3[O:18][C:15]4=[CH:16][N:17]=[C:12]([C:9]5[CH:8]=[CH:7][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=5)[CH:13]=[C:14]4[CH2:20]3)[CH2:22][CH2:23]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Product: CC(C)c1noc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.46 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH:7]([C:11]([OH:13])=O)[C:8]([OH:10])=O)[CH3:6])[CH3:2].[NH2:15][C:16]([NH2:18])=[O:17]>C(OC(=O)C)(=O)C>[O:17]=[C:16]1[NH:18][C:8](=[O:10])[CH:7]([C@H:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:11](=[O:13])[NH:15]1
Reactant: CCOC(=O)[C@@H](C)C(C(=O)O)C(=O)O
Reactant: NC(N)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)[C@@H](C)C1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A suspension of (S)-2-(1-ethoxy-1-oxopropan-2-yl)malonic acid (5 g, 25 mmol) and urea (1.8 g, 29.4 mmol) in acetic anhydride (15 mL) was placed in a microwave reactor and allowed to react under microwave irradiation at 60° C. for 30 minutes. After cooled to room temperature, the mixture was quenched by sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to afford the product (S)-ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)propanoate (2.85 g, yield 50%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:17][C:16]3[NH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:15]2[C:16]3[CH2:17][CH:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10][C:11](=[O:18])[C:12]=3[CH:13]=[CH:14]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CC(c2ccccc2)CC3=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a suspension of 60% sodium hydride (0.16 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added p-toluene sulfonylchloride (0.76 g), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 1-(4-methylphenyl)sulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (1.2 g).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1C(=O)N([Br:18])C(=O)C1>OS(O)(=O)=O>[Br:18][C:7]1[CH:8]=[C:9]([F:10])[C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
To a solution of 2,3-difluorobenzaldehyde (42 g, 0.296 mol) in H2SO4 (150 mL), was added NBS (63 g, 0.354 mol) in three portions over a period of 30 minutes at 60° C. The resulting mixture was heated for 6 hours at this temperature under N2. Work-up: the reaction mixture was poured into ice water. Petroleum ether (300 mL) was added, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with more petroleum ether (300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜0.5% EtOAc in petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (17.4 g). 1H NMR (300 MHz, CDCl3): δ 10.32 (s, 1H), 7.81-7.79 (m, 1H), 7.65-7.60 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([OH:16])[CH:15]=1)[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2.[CH2:22]1[S:24][CH:23]1[CH2:25]Cl>CC(C)=O>[OH:16][C:14]1[CH:15]=[C:2]([O:1][CH2:25][CH:23]2[CH2:22][S:24]2)[CH:3]=[C:4]2[C:13]=1[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2
Reactant: O=c1c2c(O)cc(O)cc2oc2ccc3ccccc3c12
Reactant: ClCC1CS1
Solvent: CC(C)=O
Product: O=c1c2c(O)cc(OCC3CS3)cc2oc2ccc3ccccc3c12
Temperature: 57.5 °C
Yield: 43.3 %

Procedure:
9,11-dihydroxy-12H-benzo[a]xanthen-12-one (0.1 g, 0.18 mmol) prepared in Step 1 of Examples 14 and 15, CS2CO3 (0.36 g, 0.54 mmol), and anhydrous acetone (13 mL) were charged to a dry round-bottom flask, and epithiochlorohydrin (0.2 g, 1.08 mmol) dissolved in anhydrous acetone (2 mL) was added thereto with stirring. The reaction mixture was stirred with reflux overnight at a temperature of 55 to 60° C. under a nitrogen atmosphere. Solid of the reaction mixture was filtered, removed and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give a yellow solid compound 11-hydroxy-9-(thiiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (27.3 mg, 21.7%) and a yellow solid compound 9,11-bis(thiiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (31.2 mg, 20.5%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1.C(N(CC)CC)C.CO>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:11]1[C:7](=[O:13])[CH2:8][CH2:9][C:10]1=[O:12])=[O:3])[CH3:6]
Reactant: O=C1CCC(=O)N1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Ethyl chloroformate (1.24 ml, 13.1 mmol) was added dropwise to a stirred solution of succinimide (1.0 g, 10 mmol) and triethylamine (1.6 ml, 11.5 mmol) in dimethylformamide (10 ml) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stand for 3 h. Methyl alcohol (1 ml) was added, diluted with chloroform (40 ml) and washed with water (2×20 ml). The chloroform solution was dried (Na2SO4) and concentrated in vacuum to give N-ethoxycarbonyl-succinimide (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Cl:29]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[Cl:29][C:4]1[C:5]([OH:28])=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(F)ccc3O)n2)c1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(F)cc(Cl)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 2 Step B (1.50 g, 3.79 mmol) in acetonitrile (9.5 mL) was added N-chlorosuccinimide (760 mg, 5.69 mmol), and the resulting mixture was placed in a pre-heated oil bath (90° C.). After 1 h, the reaction mixture was allowed to cool to room temperature, then was diluted with DCM, and the resulting mixture was washed with brine. The organic phase was then concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 429.9 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 12.50 (s, 1H), 8.18 (s, 1H, 8.14 (t, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.46 (dd, J=9.0, 3.0 Hz, 1H), 7.25 (dd, J=9.0, 3.0 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).