Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]3[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[CH2:5][C@@H:4]([CH2:18][CH2:19][CH2:20][NH:21][C@H:22]2[C:32]3[C:33]4[N:24]([C:25](=[O:34])[CH:26]=[N:27][C:28]=4[CH:29]=[CH:30][CH:31]=3)[CH2:23]2)[O:3]1.[BH4-].[Na+]>CO.ClCCCl>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]3[S:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[CH2:5][C@@H:4]([CH2:18][CH2:19][CH2:20][NH:21][C@H:22]2[C:32]3[C:33]4[N:24]([C:25](=[O:34])[CH2:26][NH:27][C:28]=4[CH:29]=[CH:30][CH:31]=3)[CH2:23]2)[O:3]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CCCN[C@@H]4Cn5c(=O)cnc6cccc4c65)OC3=O)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: O=C1CSc2ccc(N3C[C@@H](CCCN[C@@H]4CN5C(=O)CNc6cccc4c65)OC3=O)cc2N1
Yield: 78 %

Procedure:
A solution of the compound of Example 48 (33 mg) in MeOH/DCE (5 mL; 4:1) was treated with NaBH4 (3 mg) for 30 min then quenched with 1M. HCl (1 mL) and partitioned between DCM and an aq. NH4OH solution. The org. layer was washed with water and brine, dried over MgSO4 and purified by CC (EA/MeOH 19:1 to 9:1 containing 1% NH4OH) affording a colourless solid (26 mg; 78% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH:52]1[CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH:52]1[NH:51][C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)=[O:20]
Reactant: NC1Cc2ccccc2C1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4Cc5ccccc5C4)cc3)c(C#N)cc21
Reaction time: 3 h
Yield: 75.3 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (from Example 7, Step B) (12 mg, 0.034 mmol), HBTU (15 mg, 0.041 mmol) were diluted with N-methylpyrrolidone (1 mL) followed by the addition of 2-aminoindan (4.5 mg, 0.034 mmol), N,N-diisopropylethylamine (0.015 mL, 0.085 mmol) and DMAP (1.2 mg, 0.010 mmol). After stirring for 3 hours, the reaction was loaded directly onto a Biotage 12i cartridge eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield the title compound (12 mg, 75% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:35])[CH3:34])=[O:13].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[CH:20]=[C:19]2[C:15]=1[C:16]([CH3:36])=[CH:17][N:18]2[CH:33]([CH3:34])[CH3:35])=[O:13]
Reactant: COC(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)cn(C(C)C)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(=O)O)cc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 50 °C
Yield: 38.7 %

Procedure:
To a solution of methyl 4-[4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-3-methyl-1-(1-methylethyl)-1H-indol-6-yl]benzoate (30 mg, 0.062 mmol) in MeOH (2 mL) and THF (1 mL) was 3 N NaOH (0.031 mL, 0.185 mmol). The reaction was heated at 50° C. for 12 h, at which time it was allowed to cool to ambient temperature and treated with acidic ice water to bring pH to 6. The solid was filtered and washed several times with water and an 8:2 mixture of acidic (pH2) ice water:MeOH. Purification by reverse phase Gilson HPLC (10-80%, acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes) provided the title compound (12 mg, 0.024 mmol, 39.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (br. s., 1H) 11.48 (br. s., 1H) 8.23 (t, J=5.05 Hz, 1H) 8.02 (d, J=8.34 Hz, 3H) 7.87-7.94 (m, 4H) 7.38 (s, 1H) 7.32 (d, J=1.52 Hz, 1H) 5.87 (s, 1H) 4.91 (quin, J=6.63 Hz, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.24 (s, 3H) 2.18 (s, 3H) 2.11 (s, 3H) 1.44 (d, J=6.57 Hz, 6H). MS (ES) [M+H]+ 486.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)[OH:13])[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)c2cc3ccccc3o2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C(O)c2cc3ccccc3o2)CC1

Procedure:
Alternatively, the starting bromobenzofuran may be reacted with magnesium metal under standard conditions to prepare the corresponding Grignard reagent, benzofurylmagnesium bromide. This Grignard reagent is then reacted with the Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, to provide 1-(tert-butoxycarbonylamino)-1-(benzofurylcarbonyl)cyclopropane. This ketone is then reduced under standard conditions, typically with sodium borohydride in methanol or ethanol, to provide 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane. This alcohol is then converted to the corresponding acetate and reduced to the corresponding methylene by treatment with samarium iodide as previously described. The resulting 1-(tert-butoxycarbon-yl)-1-(benzofurylmethyl)cyclopropane is treated with acid under standard conditions to provide the compounds of the present invention. If necessary or desired, the Weinreb amide may be reduced by reaction with lithium aluminum hydride to provide the corresponding aldehyde essentially as described by Fehrentz and Castro (Synthesis, 676 (1983)). This aldehyde is then reacted with the Grignard reagent previously described to prepare 1-(tert-butoxycarbonylamino)-1-(benzofuryl(hydroxymethyl))cyclopropane, which is then subjected to the reaction conditions previously described to prepare the compounds of the present invention. The requisite Weinreb amide, N-methyl N-methoxy 1-(tert-butoxycarbonylamino)cyclopropane-1-carboxamide, may be prepared from the commercially available 1-amino-1-carboxycyclopropane by standard methods well known in the art.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[NH:5][CH:6]=1>[Pd].C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[NH:5][CH:6]=1
Reactant: Cc1c[nH]c(Cc2ccccc2[N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: Cc1c[nH]c(Cc2ccccc2N)n1
Reaction time: 4 h

Procedure:
A mixture of 23.44 g of 4-methyl-2-(2-nitrobenzyl)imidazole, 2.34 g of 10% palladium on charcoal and 234 ml of ethanol is hydrogenated at 42 psi (3 atmospheres) at room temperature for 4 hours. The catalyst is filtered and the filtrates are evaporated to dryness to give 4-methyl-2-(2-aminobenzyl)imidazole showing signals in the NMR spectrum at δ 2.09, 3.78, 6.08.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:50][C:51]1[CH:59]=[CH:58][CH:57]=[CH:56][C:52]=1[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:55][CH:53]([C:52]1[CH:56]=[CH:57][CH:58]=[CH:59][C:51]=1[Br:50])[CH3:54]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CC(O)c1ccccc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccccc4Br)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 35.6 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (85 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (139 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-bromo-α-methylbenzyl alcohol (90 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[CH:33](Br)([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C)P(=O)(N(C)C)N(C)C>[OH2:3].[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH:33]([CH3:35])[CH3:34])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[OH2:3].[OH2:3].[CH:33]([O:30][C:29](=[O:31])[CH2:28][N:24]1[C:23](=[O:32])[C:22](=[C:6]([C:7]2[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:14])[S:10][CH:11]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:26][C:25]1=[S:27])([CH3:35])[CH3:34]
Reactant: CC(C)Br
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)OC(C)C)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 27, the desired compound was prepared from 1 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylureido)thiazol-4-yl]methylene}rhodanine-3-acetic acid, 0.5 g of isopropyl bromide, 0.25 g of triethylamine and 10 ml of hexamethylphosphoric triamide. The resulting yellow crystalline product had the following physical properties.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:31]([CH3:32])[C@@H:30]2[C@@:5]([C:34]([O:36][C@@H:37]3[O:42][C@H:41]([CH2:43][O:44][C@@H:45]4[O:50][C@H:49]([CH2:51][OH:52])[C@@H:48]([O:53][C@@H:54]5[O:59][C@@H:58]([CH3:60])[C@H:57]([OH:61])[C@@H:56]([OH:62])[C@H:55]5[OH:63])[C@H:47]([OH:64])[C@H:46]4[OH:65])[C@@H:40]([OH:66])[C@H:39]([OH:67])[C@H:38]3[OH:68])=[O:35])([CH2:6][CH2:7][C@:8]3([CH3:33])[C@:13]4([CH3:29])[CH2:14][C@@H:15](O)[C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1>C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC[C@H]3O[C@@H](OC([C@]45CCC(C)(C)C[C@H]4C4=CC[C@@H]6[C@@]7(C)C[C@@H](O)[C@H](O)[C@](CO)(C)[C@@H]7[C@H](O)C[C@@]6(C)[C@]4(C)CC5)=O)C(O)[C@@H](O)C3O)O[C@@H]2CO)[C@H](O)[C@H](O)[C@H]1O>[CH3:1][C@H:2]1[C@H:31]([CH3:32])[C@@H:30]2[C@@:5]([C:34]([O:36][C@@H:37]3[O:42][C@H:41]([CH2:43][O:44][C@@H:45]4[O:50][C@H:49]([CH2:51][OH:52])[C@@H:48]([O:53][C@@H:54]5[O:59][C@H:58]([CH3:60])[C@H:57]([OH:61])[C@@H:56]([OH:62])[C@H:55]5[OH:63])[C@H:47]([OH:64])[C@H:46]4[OH:65])[C@@H:40]([OH:66])[C@H:39]([OH:67])[C@H:38]3[OH:68])=[O:35])([CH2:6][CH2:7][C@@:8]3([CH3:33])[C@:13]4([CH3:29])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5[C@H](O)C[C@]43C)[C@H]12
Agent: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC[C@H]3O[C@@H](OC(=O)[C@]45CCC(C)(C)C[C@H]4C4=CC[C@@H]6[C@@]7(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]7[C@H](O)C[C@@]6(C)[C@]4(C)CC5)C(O)[C@@H](O)C3O)O[C@@H]2CO)[C@H](O)[C@H](O)[C@H]1O
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12

Procedure:
The solution thus obtained is filtered and then concentrated, in a reactor under reduced pressure, until an aqueous phase is obtained, according to the same principle as the preceding concentration. It is then readjusted by adding ethanol in order to obtain a stabilized aqueous-alcoholic solution having a solids content of 200 g +/−20 per liter and an alcohol percentage of 35%+/−3.5% volume/volume. A prepurified phase rich in madecassoside and in terminoloside and still containing asiaticoside is thus obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:25])[O:7]1)(=[O:3])[CH3:2].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(C#N)(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH:25][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=C=Nc1ccccc1
Agent: CC(=O)C#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)Nc4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate (0.200 g, 0.572 mmol) in AcCN (3 mL) was added phenylisocyanate (0.068 g, 0.572 mmol) dropwise. The white mixture was stirred for two hours at ambient temperature, overnight at 50° C. and then concentrated to give the title compound (0.268 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C(OCC)(=O)C>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@H](Cc1ccc(N)cc1)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@H](Cc1ccc(NC(C)=O)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To (R)-(−)-3-(4-aminophenyl)-2-methoxypropionic acid (40 g) in a 0.5 L glass reactor was added ethyl acetate (80 g) and acetic anhydride (62.8 g). The mixture was stirred at 90° C. for 1 hour. Upon cooling, the solvent was removed by vacuum distillation, providing an oily residue. To this residue was added water (120 g) and ethyl acetate (120 g). After stirring for 10 min at 35° C., the layers were separated and the aqueous layer discarded. The organic layer solvent was removed by vacuum distillation. Acetone (120 g) was then added and the resulting mixture was warmed until dissolution was complete. The solution was cooled to 0° C., and the product precipitated which was collected by filtration. The solid was rinsed with acetone (20 g) and dried at 65° C. to afford 26 g of the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1>O.CO>[O:15]=[C:9]1[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][CH:10]1[CH2:11][C:12]([NH2:13])=[O:14]
Reactant: Nc1ccccc1N
Reactant: O=C1C=CC(=O)N1
Solvent: CO
Solvent: O
Product: NC(=O)CC1Nc2ccccc2NC1=O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-phenylenediamine (21.5 g, 0.2 mol) in water (450 mL) was added dropwise a solution of maleimide, (20.0 g, 0.2 mol) in methanol (180 mL) over 60 min. The mixture was then stirred at 95° C. for 2 hours followed at rt overnight. The precipitate was collected via filtration and was washed with small amount of water for a few times to yield the title compound as a pale gray solid (pure product): 1H NMR (DMSO-d6) δ=10.2 (bs, 1H), 7.37 (bs, 1H) 6.88 (bs, 1H), 6.74-6.68 (m, 3H), 6.31-6.57 (m, 1H), 5.78 (bs, 1H), 4.08-4.04 (m, 1H), 2.63 (dd, 1H, J=3.6, 15.5 Hz), 2.32 (dd, 1H, J=3.3, 15.5 Hz); HPLC (CH3CN—H2O-0.1% TFA): Rf=9.49 min.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([C@H:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH2:37]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])[CH:38]=[CH2:39]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([C@H:26]([O:28][C:45](=[O:46])[C@@H:44]([NH:43][C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH3:48])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: C[C@@H](O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O
Product: C=CCOC(=O)N[C@@H](C)C(=O)O[C@H](C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 72 %

Procedure:
In analogy to Example 5, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((R)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-2-allyloxycarbonylaminopropanoic acid and, after workup and purification, 140 mg (72%) of the title compound were isolated as a colourless foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2[C:33](=[O:42])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]2=[O:41])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: O=[N+]([O-])c1ccc(CCNCCOc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCCCN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 120 h
Yield: 85 %

Procedure:
[2-(4-Nitrophenyl)ethyl]{2-[(4-nitrophenyl)oxy]ethyl}amine (253 mg) and 2-(6-bromohexyl)-1H-isoindole-1,3(2H)-dione (1186 mg) were dissolved in DMF (4 ml) and basified by the addition of DIPEA (0.665 ml). The reaction was stirred for 120 h. The reaction mixture was evaporated to dryness and the residue dissolved in DCM, the solution was absorbed onto a pad of silica and purified on a silica cartridge (12 g) eluting with the following gradient: (A=DCM, B=methanol) t=0 min: B=10%; t=7.5 min: B=0%; t=22.5 min: B=5%. The desired product eluted at ˜15% B (isocratically) and evaporation of the solution to dryness gave the title compound (0.364 g).
Reaction SMILES: P(O[CH2:14][C@H:15]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)[C@H:17](O)[C@@H:16]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C(NC1NC(=O)NC(=O)C=1N)[C@H](O)[C@H](O)[C@H](O)CO.[CH3:52][C:53]1[N:64]=[C:63]2[C:56](=[N:57][C:58]([NH:60][C:61]2=[O:62])=[O:59])[N:55]([CH2:65][C@H:66]([OH:73])[C@H:67]([OH:72])[C@H:68]([OH:71])[CH2:69][OH:70])[C:54]=1[CH3:74]>>[CH3:14][C:15]1[CH:52]=[C:53]2[N:64]=[C:63]3[C:56](=[N:57][C:58]([NH:60][C:61]3=[O:62])=[O:59])[N:55]([CH2:65][C@H:66]([OH:73])[C@H:67]([OH:72])[C@H:68]([OH:71])[CH2:69][OH:70])[C:54]2=[CH:74][C:16]=1[CH3:17]
Reactant: Cc1nc2c(=O)[nH]c(=O)nc-2n(C[C@H](O)[C@H](O)[C@H](O)CO)c1C
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1c(NC[C@H](O)[C@H](O)[C@H](O)CO)[nH]c(=O)[nH]c1=O
Product: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C

Procedure:
Guanosine triphosphate (GTP) is converted by GTP cyclohydrolase II (rib 1 gene product) into 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5-phosphate. This compound is subsequently reduced by the rib 7 gene product to 2,5-diaminoribitylamino-2,4(1H,3H)-pyrimidine 5-phosphate and then deaminated by the rib 2 gene product to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione. Subsequently, in a reaction catalyzed by the rib 4 gene product, the C4 compound DBP is added on to result in 6,7-dimethyl-8-ribitvllumazine (DMRL), from which riboflavin is produced in the reaction catalyzed by the rib 5 gene product. The C4 compound DBP (L-3,4-dihydroxy-2-butanone 4-phosphate) is formed from D-ribulose 5-phosphate in a reaction catalyzed by the rib 3 gene product.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][CH:20]([C:22](O)=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C@H:20]([C:22]([NH:10][C:8](=[O:9])[C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[NH2:2])=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CC(C)C[C@H](N)C(N)=O
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-leucinamide hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared. This compound was then purified by column chromatography, eluted first with 1:1 EtOAc/hexane, then with 5% MeOH in methylene chloride.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]#[C:23][CH2:24][CH2:25][OH:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH:1]([N:14]1[C:15]2[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:22]=[C:23]1[CH2:24][CH2:25][OH:26])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: OCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
A solution of the crude 4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) and Cul (2.7 g, 14.1 mmol) in DMF (200 mL) was heated at 125° C. for 24 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with water (3x) and brine, and dried over MgSO4. Silica gel column chromatography (30% EtOAc/hexanes) yielded the desired 2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethanol as a yellow solid (14.5 g, 73% over 2 steps).