Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:21]2[CH:9]3[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]3[CH2:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C.O>C1(C)C=CC=CC=1>[CH3:28][N:29](/[CH:31]=[C:12]1\[CH:8]2[CH2:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:22])([CH3:1])[C:21]=3[CH:9]2[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]\1=[O:13])[CH3:30]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2CC3=C(C21)C(C)(C)CCC3
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)/C=C1/C(=O)N(C(=O)OC(C)(C)C)C2C3=C(CCCC3(C)C)CC12
Temperature: 110 °C
Yield: 64 %

Procedure:
To a solution of tert-butyl 8,8-dimethyl-2-oxo-3a,4,5,6,7,8b-hexahydro-3H-indeno[1,2-b]pyrrole-1-carboxylate (110 mg, 0.36 mmol) in toluene (2 mL) was added Bredereck reagent ((t-butoxybis(dimethylamino)methane) (0.30 mL, 1.44 mmol). The solution was heated to 110° C. for 5 h. The solution was cooled down to room temperature, and water was added. The solution was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (7/3 to 1/1) to give a white solid (83 mg, 64%). Mp 170-172° C.; LCMS (Method B) RT=1.14 min, 361 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.10 (1H, d, J=1.8 Hz), 5.27 (1H, d, J=8.1 Hz), 3.65 (1H, tt, J=8.1, 1.8 Hz), 2.99 (6H, s), 2.24 (1H, d, J=15.4 Hz), 1.75-1.97 (2H, m), 1.49-1.60 (11H, m), 1.38-1.46 (1H, m), 1.32 (1H, m), 1.19 (3H, s), 0.97 (3H, s) ppm.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[C-]#N.[Na+]>O.O1CCOCC1>[CH:1]1([O:6][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cccs1
Reactant: OC1CCCC1
Agent: [C-]#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1csc(OC2CCCC2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 25.3 %

Procedure:
To a mixture of cyclopentanol (51.1 ml, 0.56 mol) and dioxane (50 mL) was added sodium hydride (60% in mineral oil, 4.91 g, 0.12 mol) at 0–5° C. under argon. The mixture was heated at 80° C. until an homogenous solution was observed. 2-Bromothiophene (10 g, 5.9 mL, 0.061 mol) was added at 80° C., followed by cuprous iodide (11.7 g, 0.061 mol). The mixture was heated at 120° C. for 6 hours. After cooling to 20–25° C., sodium cyanide (30 g, 0.61 mol) in water (200 mL) was added. The mixture was vigorously stirred for 20 minutes, filtered, and extracted with hexane. The hexane extract was washed with water, dried (Na2SO4), and concentrated to dryness. Filtration through a column (silica, 100% hexane) gave 2-cyclopentyloxythiophene (2.6 g, 25.2%) as a colorless oil; 1HNMR (300 MHz, CDCl3) δ 6.7 (dd, J=5.7, 3.7 Hz, 1H), 6.54 (dd, J=5.7, 1.5 Hz, 1H), /86.18 (dd, J=3.7, 1.5 Hz, 1H) 4.66 (Sept, J=2.7 Hz, 1H), 1.5–2.0 (m, 8H).
Reaction SMILES: O[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1O)=O.ICI.[C:20](=[O:23])([O-])[O-:21].[K+].[K+].CN(C)C=[O:29]>>[CH2:13]1[C:3]2[CH2:4][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:23][CH2:20][O:21][C:2]=2[CH:16]=[CH:15][C:14]1=[O:29]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(c1ccccc1O)c1ccccc1O
Agent: [K+]
Solvent: ICI
Product: O=C1C=CC2=C(C1)Cc1ccccc1OCO2
Temperature: 105 °C
Yield: 90 %

Procedure:
2,2'-Dihydroxybenzophenone (10.0 g, 46.7 mmol) and diiodomethane (13.1 g, 49 mmol) was dissolved in dry dimethylformamide (180 ml). Dried, finely powdered potassium carbonate (9.2 g, 66.7 mmol) was added, and the mixture was heated at 105° C. for 16 h. After cooling to room temperature the reaction mixture was poured into ice water (500 ml). The precipitate was collected by filtration after 0.5 h, washed with water on the filter and dissolved in a mixture of ethanol (80 ml) and 4N sodium hydroxide (20 ml). The solution was stirred at reflux temperature for 1 h, cooled and diluted with water (300 ml). The formed crystalline precipitate was filtered off, washed with water (50 ml) and dried in vacuo, affording 12H-dibenzo[d,g][1,3]dioxocin-2-one as a solid (9.5 g, 90% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:16][C:17]4[CH:27]=[CH:26][C:25]5[C:20](=[C:21]([OH:31])[CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=5)[C:18]=4[N:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.C([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:16][C:17]4[CH:27]=[CH:26][C:25]5[C:20](=[C:21]([OH:31])[CH:22]=[C:23]([C:28]([NH:40][C@@H:39]([CH2:41][C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[C:38]([OH:37])=[O:48])=[O:29])[CH:24]=5)[C:18]=4[N:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)c2)cc1C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)N[C@@H](Cc6ccccc6)C(=O)O)cc(O)c54)[nH]3)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazole-7-carboxylic acid (0.05 g, 0.1 mmol) in DMF (0.5 mL) at room temperature was added phenylalanine tert butyl ester hydrochloride (0.11 mmol). A cocktail solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.021 g, 0.11 mmol), triethylamine (0.3 mmol) in DMF (0.5 mL) was added and the reaction was agitated at room temperature for 18 hours. 1 ml water was added to the reaction mixture resulting in the formation of a tan precipitate. the mixture was filtered and allowed to dry. The solid mass was transferred into vial and dissolved in 90% trifluoroacetic acid (1 mL). The solutions were agitated for 6 hrs then concentrated under reduced pressure. The residures were taked up in DMSO and subjected to Gilson HPLC purification. The title compound was abtained as solid.(0.006 g, 10%). MS(ES) m/z 556 [M+H].
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[CH:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:44](OC2C=CC([N+]([O-])=O)=CC=2)=[O:45])[CH2:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:36])=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O>[NH:37]([C:35]([O:34][CH2:33][C:30]1[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=1)=[O:36])[C@H:38]([C:44]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:45])[CH2:39][CH2:40][C:41](=[O:42])[NH2:43]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
550 mg of H-Asp(OtBu)-Phe-OCH3.HCl together with 574 mg of Z-Gln-ONP are dissolved in 2.5 ml of absolute N,N-dimethylformamide and stirred with 0.20 ml of triethylamine for 15 hours at 30°-33° C. bath temperature. Thereafter the product is extracted by shaking with a large amount of ethyl acetate as described under 19 and the solution is dried and evaporated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][N:22]=1>CN(C=O)C>[CH2:27]([C:24]1[CH:23]=[N:22][C:21]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[N:26][CH:25]=1)[CH3:28]
Reactant: NCCc1ccc(O)cc1
Reactant: CCc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NCCc2ccc(O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
Tyramine (5.52 g, 0.040 mol) in 40 ml of anhydrous DMF was treated with diisopropylethylamine (6.1 ml, 0.035 mol). After stirring at rt for 15 minutes, 2-chloro-5-ethylpyrimidine (4.25 ml, 0.035 mol) was added and the mixture heated at 80° C. for 14 hours. The solution was allowed to cool to room temperature and was partitioned between equal volumes of water and ethyl acetate. The aqueous phase was washed with ethyl acetate and the combined organic phases were dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate-hexane to afford the title compound as a colorless solid (4.94 g; 58% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1CC[CH:33]([N:36]=[C:37]=NC2CCCCC2)CC1.CNC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([N:36]([CH3:37])[CH3:33])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A mixture of 15 g of (2S,4R)-1-(benzyloxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid, 7.64 g of HOBT and 11.65 g of DCC in 250 ml of DCM is stirred for 1 hour at RT. The reaction mixture is cooled on an ice bath, dimethylamine gas is added by sparging for 10 minutes and this mixture is stirred for 3 hours at RT. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up in saturated Na2CO3 solution and extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained in the form of an oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ccccc3c(=O)[nH]2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c(-c2cccc(O)c2)nc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 2-(3-methoxyphenyl)quinazolin-4(3H)-one (11.6 g, 45.98 mmole) was added of CH2Cl2 (120 mL) and the mixture was cooled to −78° C. Then, a 1 M solution of BBr3 in CH2Cl2 (60 mL, 60.0 mmol) was added drop wise and the reaction was stirred at −78° C. for 1 h and then ambient temperature for 3 h. The reaction was re-cooled to −78° C. and cautiously quenched with MeOH (20 mL). The ice bath was removed and the system allowed to stir at ambient temperature for 0.5 h. The pH was adjusted to 7 with 10% w/w NaHCO3 solution. The solid was filtered, washed with ether, dried and then azeotroped from toluene (3×) and dried under high vacuum overnight to give 2-(3-hydroxyphenyl)quinazolin-4(3H)-one. (11.0 g, mmol, 100%).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCO
Reactant: O=C1C=CC(O)N1
Product: CCCCCCOC1C=CC(=O)N1
Temperature: 85 °C

Procedure:
A mixture of 2.5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 75 cm3 of 1-hexanol and 1.3 g of Amberlite IR 120 H is heated to 85° C. for 2 hours. After allowing to cool to ambient temperature, the resin is filtered off and the solvent is evaporated under reduced pressure. The residue is distilled, and 3.4 g of the expected product is obtained. b.p. 120°-125° C. under 0.4 mbar.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:19])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[O:6][CH:7]=1.[CH2:20]=[O:21].[OH-].[Na+]>O1CCOCC1>[OH:1][C:2]1[C:3](=[O:19])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[O:6][C:7]=1[CH2:20][OH:21]
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.5 %

Procedure:
To a stirred solution of N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (8-01) (1.1 g, 3.92 mmol) in dioxane (20 mL) were added 37% formaldehyde solution (0.47 mL, 4.69 mmol) and aqueous NaOH (1.95 mL, 3.92 mmol, 2M) and the mixture was stirred for 6 h at room temperature. After completion of the reaction, it was concentrated under vacuum to get a crude compound. It was then purified using normal column chromatography to get N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzene sulfonamide (9-01) (470.0 mg, 38.57%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[H][H]>O1CCCC1.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1F

Procedure:
A solution of 2,5-difluoronitrobenzene in tetrahydrofuran containing Raney nickel catalyst, in a Parr shaker, was treated with hydrogen at room temperature to give 2,5-difluoroaniline (2A).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.COCCOC.[NH3:50]>N.CO>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:50])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: N
Solvent: CO
Solvent: COCCOC
Product: Nc1ncnc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 67 %

Procedure:
A solution of 9 (1.00 g) in DME/NH3 (50 ml) was heated at 80° C. in a steel bomb for 24 hours. After cooling, the solvent was evaporated and the solid obtained was stirred in NH3 /MeOH (100 ml) overnight. After the evaporation of the solvent, the residue was dissolved in water (50 ml), washed with CHCl3 (2×25 ml) and ether (2×25 ml). The water layer was evaporated and the residue crystallized from water to give pure 10 (0.30 g, 67%) as white crystals: m.p. 225° C. (dec).
Reaction SMILES: [CH:1](=[C:8]1/[C:9](=[O:18])[NH:10][C:11]2[C:16]/1=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[CH2:23]([O:22][C:20]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)/[C:8](=[CH:1]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)/[C:9]1=[O:18])=[O:21])[CH3:24]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)/C(=C\c2ccccc2)c2ccc(Cl)cc21
Yield: 104 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-3-benzylidene-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 5.87 mmol) was reacted with ethyl chloroformate (0.83 mL, 8.8 mmol) and triethylamine (1.64 mL, 12 mmol) in dichloromethane to give E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 2.0 g, 100%).
Reaction SMILES: [C:1]([C:6]1([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:8][CH2:7]1)([O:3]CC)=[O:2].O.[OH-].[Li+]>C(O)C.O.O1CCCC1>[C:1]([C:6]1([S:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(SCc2ccc(OC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CSC2(C(=O)O)CC2)cc1
Yield: 96.2 %

Procedure:
Dissolve 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclopropane (0.310 g, 1.16 mmol) in 95% ethanol (6 mL), water (3 mL), and tetrahydrofuran (6 mL). Treat with lithium hydroxide monohydrate (420 mg, 10mmol). Stir at a gentle reflux for 6 hours and evaporate the solvent in vacuo. Add water (50 mL) and wash with ether (50 mL). Acidify the aqueous phase and extract into methylene chloride (50 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to give 1-(carboxy)-1-(4-methoxybenzylthio)cyclopropane as a pale yellow solid (266 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2Cl.[CH2:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:17][CH3:18])[CH2:20][CH2:21]1
Reactant: Clc1ccc2c(Cl)c3ccccc3nc2c1
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(Nc2c3ccccc3nc3cc(Cl)ccc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 3,9-dichloroacridine (J. Med. Chem. 1985, 28. 940-944) and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=340).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](OC(C)(C)C)=[O:52])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C:62]([NH:64][C@H:65]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)C(O)=O)=[O:63].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:8])[CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](=[O:52])[C@H:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[C:69]7[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=7)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])=[O:4]
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c54)cc2-3)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (218 mg, 0.27 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (3 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (73 mg, 0.35 mmol) and COMU (127 mg, 0.30 mmol). To the resulting solution was added diisopropylethylamine (0.141 mL, 0.81 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(1R)-2-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (121 mg, 50%). LCMS-ESI+: calculated for C50H56N8O8: 896.4; observed [M+1]+: 897.5.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:8][NH+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2F)[C:12](=[O:20])[CH:11]=[N:10]1)([OH:4])=[O:3].Cl.[Li+].[OH-:27]>>[Cl-:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:8][NH+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[OH:27])[C:12](=[O:20])[CH:11]=[N:10]1)([OH:4])=[O:3]
Reactant: O=C(O)c1cc(C[NH+]2N=CC(=O)c3cccc(F)c32)ccc1F
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Product: O=C(O)c1cc(C[NH+]2N=CC(=O)c3cccc(O)c32)ccc1F

Procedure:
A solution of D5 in 9% LiOH (0.05 M) was heated at 160° C. under microwaves irradiation for 15 min. The aqueous phase was made acidic with 37% HCl. The resulting precipitate was collected by filtration affording the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Br)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][S:13]C.[Na].CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CSC
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CSc1cc(Br)cc(C(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol), sodium methyl sulfide (1.4 g, 20 mmol), and dimethyl sulfoxide (10 mL) was sealed in a microwave tube and heated with an oil bath at 100° C. for 4 h. TLC indicated completion of the reaction. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was used for the next step reaction without purification. 1H NMR (400 MHz, CDCl3): δ 7.97 (t, 1H, J=1.6 Hz), 7.87 (t, 1H, J=1.6 Hz), 7.57 (t, 1H, J=1.6 Hz), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:22]([C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (103 g, 0.35 mol) and tosyl chloride (66.7 g, 0.35 mol) were dissolved in toluene (517 g) and then cooled to 0° C. To the mixture was added dropwise triethylamine (35.5 g, 0.35 mol) at 0° C. over 90 min. The mixture was further kept at 0° C. for 4 hrs. The reaction mass was washed with 5% hydrochloric acid (255 g) and 5% aqueous sodium bicarbonate (294 g) and then concentrated at 35° C. under reduced pressure until the weight of the toluene layer reached to 243 g. After cooling to −10° C., to the concentrate was added dropwise n-hexane (310 g) over 3 hrs. Deposited crystals was filtered and dried to give N-Boc-O-tosyl L-tyrosine methyl ester 4 (147 g, yield 92%) as white crystals.