Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]1[CH2:18][C:16](=O)[C:14](=O)[CH2:13][CH2:12]1>C(O)C.C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]3[C:12](=[CH:11][CH:18]=[C:16]4[C:14]=3[NH:9][C:6]3[C:5]4=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=3)[C:5]=2[CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccc2[nH]c3c(ccc4c5cc(Br)ccc5[nH]c43)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
4-Bromophenylhydrazine hydrochloride (99%; 10.44 g, 1 eq) is introduced into a solution of 1,2-cyclohexadione (98%; 5.4 g, 1 eq) in absolute ethanol (50 ml). After adding 20 drops of glacial acetic acid, the mixture is stirred at room temperature for 1 h and then at 80° C. for 4 h. Then a further 5.3 g of 99% 4-bromophenylhydrazine hydrochloride are added to the reaction and, after a further 6 h at 80° C., another 5.3 g of 99% 4-bromophenylhydrazine hydrochloride are added. The reaction is stirred overnight. After 22 h, the mixture becomes viscous, so 150 ml of absolute ethanol and a further 3 g of 99% 4-bromophenylhydrazine hydrochloride are added. After a further 2 h at 80° C., the mixture is worked up. For this purpose, the solvent is distilled off. The residue is introduced gradually into polyphosphoric acid (50 g), heated to 120° C. and stirred for 1 h. The reaction output is added cautiously to ice-water and neutralized with 2M NaOH. The precipitate is filtered off and washed with distilled water. The residue is dried under reduced pressure. After recrystallization in glacial acetic acid, 5.8 g are obtained. Yield: 29.7%
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=1.[F:15][C:16](I)([F:18])[F:17]>N1C=CC=CC=1.[Cu]>[N+:12]([C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([C:16]([F:18])([F:17])[F:15])=[CH:11][CH:10]=2)[CH:5]=1)([O-:14])=[O:13]
Reactant: FC(F)(F)I
Reactant: O=[N+]([O-])c1ccc2ccc(I)cc2c1
Agent: [Cu]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2ccc(C(F)(F)F)cc2c1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 2-iodo-7-nitronaphthalene (1 g, 3.34 mmol), trifluoromethyliodide (0.328 mL, 4.01 mmol) and copper powder (2.55 g, 40.1 mmol) in pyridine (20 mL) in a sealed tube is heated with stirring at 120° C. for 20 hours. After cooling, the reaction mixture is filtered and extracted with EtOAc. The organic extracts are washed with water, 0.1 M citric acid solution and dried (Na2SO4). Concentration and purification of the residual oil by flash chromatography on silica gel (2:1 hexanes/EtOAc) gives 2-nitro-7-trifluoromethylnaphthalene as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[C:10]([C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(COC)OC>[C:1]1([C:7]2[N:12]=[C:11]3[C:13]([O:18][C:16](=[O:17])[C:10]3=[CH:9][CH:8]=2)=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Product: O=C1OC(=O)c2nc(-c3ccccc3)ccc21
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 5.56 g (22.9 mmol) of 6-phenyl-2,3-pyridinedicarboxylic acid and 7 ml (121.8 mmol) of acetic anhydride in 25 ml of dimethoxyethane (DME) is added 3.7 ml (45.7 mmol) of pyridine. A small exotherm ensues, and the anhydride begins to precipitate. After one hour, the reaction mixture is diluted with ether and hexane to the cloud point, chilled in an ice bath, and filtered. The solid is washed with ether to give 4.73 g of the desired anhydride as a white solid, mp 187°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.C([BH3-])#N.[Na+].Cl.[BH4-]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][OH:6]
Reactant: ON=Cc1ccccc1Cl
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: ONCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
A solution of 26.0 grams (0.7 mole) of 2-chlorobenzaldoxime and a trace of methyl orange indicator in 200 ml of methanol was stirred in a flask equipped with a drying tube and two dropping funnels. A solution of 13.2 grams (0.21 mole) of sodium cyanoborohydride in 70 ml of methanol and a solution of 190 ml of methanolic 2 N hydrochloric acid were both added dropwise with the rates of addition adjusted to keep the pH of the reaction mixture at about 3.0 as shown by the pink color of the indicator. The borohydride solution was added over a period of about thirty minutes: addition of the acid solution was complete after about four and one half hours. The reaction mixture was stirred at room temperature for about 16 hours and then concentrated under reduced pressure to a solid residue. The solid was slurried with 200 ml of water. The mixture was adjusted to pH 9 with aqueous 6 N potassium hydroxide and then extracted with one portion of 300 ml of chloroform. The organic layer was washed with an aqueous solution saturated with sodium chloride and then dried with sodium sulfate. The solution was filtered from the sodium sulfate, and the filtrate was concentrated under reduced pressure to give a residual solid. The solid was twice recrystallized from 15% ethyl acetate in hexane to give 13.7 grams of N-(2-chlorophenylmethyl)hydroxylamine; mp 73°-75.5° C. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:29][CH2:30]1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Reactant: C1COCCN1
Product: O=C(CCCCN1CCOCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCOCC3)ccc1-2

Procedure:
By the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, 34.9g (0.4 mole) of morpholine were reacted to give the desired product which was recrystallized twice from methylene chloride-methanol. M.P. 134°-136.5° C, λmax0.1NHCl 325, Elcm1% 776.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([O:11][CH2:19][CH3:20])=[C:8]([CH3:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: CCI
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(C)cc([N+](=O)[O-])cc1C
Yield: 97.7 %

Procedure:
A mixture of 10 g (0.0598 mol) of 4-nitro-2,6-dimethylphenol, 16.5 g (0.1196 mol) of K2CO3 and 18.6 g (0.1196 mol) of ethyl iodide in 100 ml of acetonitrile was refluxed for 2.5 hours. The solid material was removed by hot filtration and was then washed with hot acetonitrile. The combined organic phase was evaporated and the resulting residue dissolved in ether. The ether phase was washed with water, dried (Na2SO4) and evaporated yielding 11.4 g (98%) of the product, M.p. 56° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].C(OC)(OC)OC.Cl.[CH2:18](O)[C:19](=[CH2:21])[CH3:20].CS(O)(=O)=O>CC(O)=O.CO>[CH3:1][C:2]1([CH2:20][C:19]([CH3:21])=[CH2:18])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9]
Reactant: C=C(C)CO
Reactant: CC1CCCC(C)C1=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: CO
Product: C=C(C)CC1(C)CCCC(C)C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2,6-Dimethyl-cyclohexanone (1 kg, 4 mol), trimethyl orthoformate (TMOF, 880 g), and methanol (800 mL) were charged to a 5 L reaction flask. HCl was added quickly. Reaction exothermed and the temperature increased from 14° C. to 20° C. The reaction mixture was heated to 60° C. and aged for 7 hours. When the reaction was about 75% complete, the reaction mixture was quenched with NaOCH3 (25%, 25 g), heated to 90° C., and applied to a Bidwell-Sterling trap. The reaction mixture was then cooled to room temperature followed by sequential addition of methallyl alcohol (1.25 Kg, 8.5 moles), HOAc (50 g), and methane sulfonic acid (MSA, 10 g). The resulting mixture was heated to 110° C., applied to a Bidwell-Sterling trap, and aged for 4 hours until gas chromatograph analysis indicated that the reaction was 95% completed. The reaction mixture was then cooled and washed with saturated sodium carbonate solution (3 L) to provide the crude product 2,6-dimethyl-2-(2-methyl-allyl)-cyclohexanone.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20]>>[CH2:1]([NH:8][C:9]([NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:35][CH2:36][CH3:37])[O:38][CH2:39][CH3:40])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:20])=[O:15])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 66 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: Br[C:2]([F:19])([F:18])[S:3]([C:6]1[N:10]=[CH:9][N:8]([C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1)(=[O:5])=[O:4].[CH2:20](SC1SCCN=1)[CH:21]=[CH2:22].P([O-])([O-])(O)=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[CH2:13]([N:12]([CH2:15][CH3:16])[C:11]([N:8]1[CH:9]=[N:10][C:6]([S:3]([C:2]([F:19])([F:18])[CH2:22][CH:21]=[CH2:20])(=[O:5])=[O:4])=[N:7]1)=[O:17])[CH3:14]
Reactant: CCN(CC)C(=O)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Reactant: C=CCSC1=NCCS1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(F)(F)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To a stirred solution of 10 g (0.028 mol) 3-(bromodifluoromethylsulfonyl)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole, prepared as in Example 1, and 8.81 g (0.055 mol) 2-(2-propenylthio)-2-thiazoline in a mixture of 30 ml dimethylformamide and 20 ml water at 0° C., was added 5.9 g (0.042 mol) sodium hydrogen phosphate and 7.23 g (0.042 mol) sodium dithionite. After 2 h, the reaction mixture was diluted with 100 ml water and extracted with ethyl acetate (3×100 ml). The combined resulting organic layers were washed with saturated sodium chloride solution, dried over MgSO4 and evaporated. Preparative LC purification of the residue with 40% ethyl acetate-hexane gave 2.59 g (29% yield) of the desired product as a colorless oil having n D 25 = 1.4896 .
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[CH3:12][N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][C:17]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 75 °C

Procedure:
A mixture of phthalic anhydride (30 g.), N,N-dimethylaniline (60.5 g.), aluminum chloride (60 g.) and chlorobenzene (180 g.) was heated (to 75° C.) during one hour, then cooled. Ice (500 ml.) was added, the chlorobenzene layer was separated and the chlorobenzene was steam distilled. Addition of base to a solution of the residue in dilute sulfuric acid afforded 2-(4-(dimethylamino)benzoyl)benzoic acid (IV: Y2 = Z4 = Z"5 = Z"6 = Z7 = H, Y'4 = (CH3)2N).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([NH2:21])[CH2:8][S:9][S:10][CH2:11][C@H:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([N:20]([S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:11][S:10][S:9][CH2:8][C@H:7]([NH2:21])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CSSC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H](N)CSSC[C@@H](C(=O)OC(C)(C)C)N(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
Preparation in analogy to example 6a from 1 g (2.35 mmol) of (R)-cystine-bis-tert-butylester and 0.83 g (4.7 mmol) benzenesulfonic acid chloride. Yield: 1.5 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([OH:16])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Cl.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1([NH2:27])[CH2:26][O:25][CH2:24]1>>[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1([NH:27][C:14]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:6]=2)=[O:16])[CH2:26][O:25][CH2:24]1
Reactant: NC1(c2nccs2)COC1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)n1
Agent: Cl
Product: O=C(NC1(c2nccs2)COC1)c1ccc(Br)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 282a) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=438.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[NH:7][C:8]([C:11]2[CH:24]=[C:23]3[O:25][CH2:26][C:20]4[C:21]5[C:22]3=[C:13]([CH2:14][O:15][C:16]=5[CH:17]=[C:18]([C:27]3[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5C(OC(C)(C)C)=O)=[N:29][CH:28]=3)[CH:19]=4)[CH:12]=2)=[CH:9][N:10]=1.N1CCC[C@H]1C1NC(C2C=C3COC4C5=C(C=C(C6NC([C@@H]7CCCN7)=NC=6)C=4)COC(C=2)=C35)=CN=1.[CH3:80][O:81][C:82]([NH:84][C@@H:85]([CH:89]([CH3:91])[CH3:90])[C:86](O)=[O:87])=[O:83].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH3:90][CH:89]([CH3:91])[C@H:85]([NH:84][C:82](=[O:83])[O:81][CH3:80])[C:86](=[O:87])[N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:30]1[NH:31][C:27]([C:18]2[CH:19]=[C:20]3[CH2:26][O:25][C:23]4[C:22]5=[C:13]([CH:12]=[C:11]([C:8]6[NH:7][C:6]([C@@H:2]7[CH2:3][CH2:4][CH2:5][NH:1]7)=[N:10][CH:9]=6)[CH:24]=4)[CH2:14][O:15][C:16]([CH:17]=2)=[C:21]35)=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6CCCN6)[nH]5)cc(c2-4)OC3)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1nc([C@@H]2CCCN2)[nH]c1-c1cc2c3c(c1)OCc1cc(-c4cnc([C@@H]5CCCN5)[nH]4)cc(c1-3)OC2
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6CCCN6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Temperature: 25 °C
Yield: 12 %

Procedure:
The mixture of (S)-tert-butyl 2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and 2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene obtained in the previous step was dissolved in dimethylformamide (6 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (194 mg, 1.11 mmol), HATU (309 mg, 0.81 mmol), and N-methylmorpholine (0.24 mL, 2.2 mmol). The reaction was stirred at room temperature for thirty minutes, and then quenched by the addition of formic acid (0.05 mL). The reaction was concentrated and the resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H2O+0.1% TFA) to yield methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (59 mg, 12%) as the tris-TFA salt. Also isolated from the reaction were (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (124 mg, 23%) and dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno-[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (50 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[O:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1cc2ccccc2o1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1cc2ccccc2o1
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-bromoacetylbenzo[b]furan (960 mg) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 50 min the reaction mixture was cooled to 3° C. and the solid collected. The filtrate was evaporated and the residue was subjected to preparative thin-layer chromatography developing with chloroform-ethanol (50:1) (4 runs) which gave a yellow solid. The two solids were combined and crystallised twice from acetone to give the title pyrimidinone (415 mg) m.p. 202°-205° C., λmax (EtOH) 227.5 nm (ε14,060), 298 nm (ε20,930).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@H]2O)[C@@H]1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OS(C)(=O)=O)[C@@H]1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside (420 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at 0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-L-glucofuranoside as a colorless, 669 mg, 95% yield, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:10]([CH3:12])[CH3:11]>CCO.[Pd]>[CH2:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccccc1C=C(C)C
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CC(C)C
Yield: 84 %

Procedure:
A solution of 1-(2-methoxyphenyl)-2-methylpropene (9a) (3.37 g, 20.8 mmol) and 10% Pd/C (300 mg) in 100 ml of anhydrous EtOH at rt was hydrogenated at 60 psi until complete conversion was determined by GC/MS (9 h). The reaction mixture was filtered through celite and concentrated in vacuo to yield 2.87 g of a clear oil (84%): 1H NMR (500 MHz, CDCl3) δ 0.90 (d, J=6.6 Hz, 6H), 1.92 (m, 1H), 2.49 (d, J=7.1 Hz, 2H), 3.82 (s, 3H), 6.88 (m, 2H), 7.10 (d, J=8.9 Hz, 1H), 7.18 (t, J=8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 22.55, 28.64, 39.43, 55.22, 110.27, 120.07, 126.80, 130.22, 130.80, 157.70; HRMS (EI) Calcd for C11H16O: 164.1201. Found 164.1207.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7]N)=[O:6])[CH2:3][OH:4].Cl.O1CCOCC1.N(OCCC(C)C)=O.[N-]=[N+]=[N-].N[C@H:38]([C:43]([NH:45][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41].Cl>CN(C)C=O.NN.O.C(N(CC)CC)C>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:5]([NH:7][C@H:38]([C:43]([NH:45][C@H:46]([C:49]([O:51][CH3:52])=[O:50])[CH2:47][OH:48])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:6])[CH2:3][OH:4]
Reactant: NNC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C
Agent: CC(C)CCON=O
Agent: Cl
Agent: NN
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 18 h

Procedure:
3.19 Grams of Z-Ser-NHNH2 was dissolved in 25 ml of dimethylformamide, and 6.30 ml of 6N-hydrochloric acid/dioxane was added to the solution, cooled to -15° C., then 1.69 ml of isoamyl nitrite was added thereto. After the reaction mixture shows a negative reaction in hydrazine-test, 1.76 ml of a cold dimethylformamide solution with 5.29 ml of triethylamine was added drop by drop in small amount to neutralize the reaction mixture. This reaction mixture containing an azide product was added to 20 ml of a cold dimethylformamide solution containing H-Leu-Ser-OCH3.HCl obtained in the above-mentioned step 14(a) and 1.60 ml of triethylamine, and the whole mixture was stirred at -10° to -15° C. for 2 hours, next at 4° C. for 18 hours. Dimethylformamide was removed by distillation under a reduced pressure, the residue obtained was solidified by adding water, reprecipitated from methanol-ethyl acetate to obtain 4.11 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.C(OC([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=O)(C)(C)C.CN1CCOCC1>C1COCC1>[NH2:31][C@H:32]([C:34]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)=[O:35])[CH3:33]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc2c(c1)C(=Cc1ccc(O)c3ncccc13)C(=O)N2
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](N)C(=O)Nc1ccc2c(c1)C(=Cc1ccc(O)c3ncccc13)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-amino-3-(8-hydroxyquinol-5-ylmethylen)-2-oxindole (497 mg, 1.64 mmol) and of t-butoxycarbonyl-L-alanine (360 mg, 1.9 mmol in 80 ml of THF were added 950 mg (1.82 mmol) of benzotriazol-1-yloxytripyrrolidinophosphoniun hexafluorophosphate and 0.2 ml (1.87 mmol) of N-methylmorpholine. The reaction was maintained at room temperature for 4 h. After evaporation of the solvent the residue was purified by flash chromatography with cyclohexane/ethyl acetate 3:7. The evaporated eluant was solubilized in dichloromethane, 10 ml of trifluoroacetic acid was added and the mixture stirred at room temperature for 1 h. After the usual workup pure title compound was obtained in 80% yield (491 mg).