Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]4)=[CH:8][O:9][C:5]=2[CH:4]=1.Cl.Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: COc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc2c1

Procedure:
This compound is synthesized from 4-(6-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (120) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: C1C=CC=CC=1.CI.[OH-:9].[Na+].C([N+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])CCCC)CCC>O>[N:15]1[C:20]2[C:26]([CH:27]=[CH:23][C:22](=[O:9])[CH:21]=2)=[CH:25][CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: [OH-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: c1ccccc1
Product: O=C1C=CC2=CC=NC2=C1
Reaction time: 0.5 h

Procedure:
A mixture of 5 g of 3,4-dihydro-1H-cyclohept[c,d] indol-6-one, 50 ml of benzene, 2.5 ml of methyl iodide, 25 ml of 5 N sodium hydroxide solution and 9.2 g of tetra-n-butyl ammonium acid sulfate was stirred for 30 minutes under an inert atmosphere at 40°-45° C. and the mixture was diluted with water. The decanted aqueous phase was extracted with ethyl acetate and the organic phase was washed with N hydrochloride acid, with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 95-5 chloroform-ethyl acetate mixture to obtain 6.5 g of raw product. The latter was crystallized from isopropanol to obtain 5.15 g of 1-methyl-1,3,4,5-tetrahydro-6H-cyclohept [c,d,] indol-6-one melting at ≃70° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]([CH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:19]([C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:27][CH2:28]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2nnc(Cc3ccncc3)c3ccccc23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g (3.91 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67.A1 in WO 98/35958) and 1.82 g (11.7 mmol) 4-tert-butylcyclohexylamine (trans-/cis-mixture) is stirred overnight at 120° C. The cooled reaction mixture is then distributed between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic phase is washed with water and brine, dried (MgSO4) and evaporated and the residue purified on silica gel by flash chromatography using dichloromethane/methanol (9:1) yielding the title compound as a trans-/cis-mixture: FAB MS (M+H)+=375. Separation of the isomers by reversed phase medium pressure chromatography (CH3CN/H2O/trace of TFA) gives the cis-isomer (m.p. 64-65° C.) followed by the trans-isomer (m.p. 132-134° C.).
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[C:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:18]=[C:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:12][CH:11]=1.C1(C)C=CC(S(C#N)(=O)=O)=CC=1.C(OCC)C>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([C:1]#[N:4])=[C:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[N:18]=[C:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:12][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C#N
Reaction time: 1 h

Procedure:
Lithium diisopropyl amide (LDA) (5.25 mL of a 2 M solution in THF, 0.0105 mol) is added dropwise to a cooled solution (−70° C.) of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (4.24 gram, 0.010 mol) in anhydrous THF (80 mL) in a nitrogen atmosphere and the resulting mixture is stirred for one hour. A solution of p-toluenesulfonyl cyanide (1.88 gram, 0.011 mol) in anhydrous THF (20 mL) is added dropwise and the resulting red solution is stirred for one hour at −70° C. and then allowed to attain room temperature. Diethyl ether is added and the resulting solution is quenched with water and filtered over hyflo. The organic layer is collected and washed with water, dried over MgSO4, filtered and concentrated in vacuo to give an oil. This oil is purified by column chromatography (dichloromethane, silicagel) to give 3.4 gram of tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate. Recrystallisation from diisopropyl ether gave crystalline tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (2.57 gram, 57% yield). Melting point: 210-212° C.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.C[NH:47][CH2:48][CH2:49]C#N>>[C:48]([CH2:49][CH2:39][N:8]([CH3:6])[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])#[N:47]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CNCCC#N
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C)CCC#N)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (150 mg) described in Example 769 and 3-methylaminopropionitrile (90 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (26 mg) was obtained.
Reaction SMILES: [C:1]([NH:6][C:7](=[NH:10])OC)([O:3][CH2:4][CH3:5])=[O:2].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>CO>[C:1]([NH:6][C:7]([NH:21][CH2:20][CH2:19][S:18][CH2:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:11])=[NH:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)NC(=N)OC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CO
Product: CCOC(=O)NC(=N)NCCSCc1[nH]cnc1C

Procedure:
A solution of N-carbethoxy-O-methylisourea (1.46 g.) and 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (1.71 g.) in methanol (25 ml) was stirred at room temperature for 7 days. The white solid formed during the reaction was collected and recrystallised from methanol to give N-carbethoxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine m.p. 196°-197°.
Reaction SMILES: [CH3:1][S:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][S:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: CSSc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSSc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 39a (50 mg, 0.3 mmol) in dry CH2Cl2 (3 ml) was added triethylamine (127 μL, 0.9 mmol, 3 eq.), followed by acetyl chloride (32 μL, 0.45 mmol). The reaction was stirred at RT for 1 hr., then was diluted with dichloromethane, washed with water, then 5% aq. HCl, then 5% aq. NaHCO3. Dried over MgSO4, then concentrated in vacuo to give a yellow oil which solidified on standing. Chromotography (1:1 petroleum ether:ethyl acetate) gave 18 mg (29%) as a light brown solid. 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 4H); 2.41 (s, 3H); 2.16 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([NH:21]C(OC(C)(C)C)=O)([CH3:20])[CH3:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[NH2:21][C:18]([CH3:20])([CH3:19])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:29]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propionic acid (10 g) in tetrahydrofuran (20 mL) were added 1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzo-triazole (8.02 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (11.4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of n-hexane and ethyl acetate (1/1) (40 mL) at 60° C. with heating, and the solution was stirred at room temperature overnight. To the mixture was added the same solvent (30 mL), and the mixture was further stirred overnight. The precipitated crystals were collected by filtration, and washed with the same solvent and dried under reduced pressure to give 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (13.5 g). To a solution of the obtained 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]-piperazine (5 g) in tetrahydrofuran (30 mL) was added hydrochloric acid (4 mol/L 1,4-dioxane solution, 40 mL), and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: COC([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH:7]([CH2:17][CH:18]=[CH2:19])[C:6]1=[O:20])=O.[Cl-].[Li+]>CS(C)=O.O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH2:5][C:6](=[O:20])[CH:7]([CH2:17][CH:18]=[CH2:19])[CH2:8]2
Reactant: C=CCC1Cc2cccc(OC)c2C(C(=O)OC)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC1Cc2cccc(OC)c2CC1=O
Temperature: 125 °C
Yield: 94.1 %

Procedure:
To a solution of 10.3 g (37.6 mmol) of 1,2,3,4-tetrahydro-8-methoxy-2-oxo-3-(2-propenyl)-1-naphthalene carboxylic acid methyl ester in 26.3 mL of DMSO and 1.1 mL of water was added 1.9 g (45.1 mmol) of lithium chloride. The reaction mixture was heated at 125° C. (bath temperature) for five hours. TLC analysis showed no starting material remaining. The mixture was cooled to room temperature and extracted with ethyl acetate (1 L). The organic layer was washed with 10% aqueous calcium sulfate (an efficient way of removing DMSO from organic layer), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by liquid chromatography on 800 g silica gel 60 (230-400 m), eluting with hexane-ethyl acetate (3:1), and collecting 40 mL fractions. Fractions 26-53 gave 7.65 g (94%) of pure title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[C:23]([OH:27])=[C:22]([Br:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[O:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([Br:28])[C:23]([OH:27])=[C:24]([Br:26])[CH:25]=3)[C:29](=[O:31])[N:45]3[CH2:44][CH2:43][N:42]([CH:39]4[CH2:40][CH2:41][O:36][CH2:37][CH2:38]4)[CH2:47][CH2:46]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: C1CN(C2CCOCC2)CCN1
Product: O=C(O[C@H](Cc1cc(Br)c(O)c(Br)c1)C(=O)N1CCN(C2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Prepared analogously to Example 81 from 100 mg (0.16 mmol) (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30.6 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine, the reaction mixture being stirred overnight at RT.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.N[C@H](CC1C=C(OC)C(OC)=C(OC)C=1)C(O)=O>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Agent: COc1cc(C[C@@H](N)C(=O)O)cc(OC)c1OC
Product: COc1cc(C[C@@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using (R)-2-amino-3-(3,4,5-trimethoxyphenyl)-propionic acid (3,4,5-OCH3-phe-OH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([F:33])([F:32])[F:31])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1([N+:27]([O-])=O)[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21][CH2:20]1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn]>[CH2:1]([O:8][C:9]1[C:10]([C:30]([F:31])([F:33])[F:32])=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1([NH2:27])[CH2:20][O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24]1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(c2ccc3c(C(F)(F)F)c(OCc4ccccc4)ccc3c2)([N+](=O)[O-])CO1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(C)OCC(N)(c2ccc3c(C(F)(F)F)c(OCc4ccccc4)ccc3c2)CO1
Temperature: 23 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
5-(6-(benzyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-2,2-dimethyl-5-nitro-1,3-dioxinane (2.00 g, 0.00433 mol) was dissolved in acetic acid (20 mL, 0.4 mol), followed by zinc (2.834 g, 0.04334 mol) in small portions at 23° C. The reaction mixture was then allowed to stir at 23° C. for 4 hours. Excess of acetic acid was removed, and the residue was treated with DCM, and filtered. The organic layer was then treated with NaOH (2N, 2 mL), and separated. The organic layer washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4. Removal of the solvent gave a pure product (1.88 g, 100%). MS (ES, M+1): 432.30.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.Cl.[NH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]2=[O:10]
Reactant: CCOC(=O)CCN
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCN1C(=O)c2ccc(C)cc2C1=O
Temperature: 130 °C
Yield: 80.4 %

Procedure:
A solution of 4-methylphthalic anhydride (21.3 g, 0.13 mol), ethyl 3-aminopropionate hydrochloride (20.2 g, 0.13 mol), and triethylamine (19 mL) in NMP was stirred at ambient temperature for 3 days, and heated to 130° C. for 3 hours. The mixture was diluted with water (300 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N hydrochloric acid (2×50 mL), sodium bicarbonate solution (2×50 mL), dried (MgSO4), and concentrated to give 27.3 g yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:39][O:40][C:41](=[O:52])[CH:42]([NH2:51])[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:39][O:40][C:41](=[O:52])[CH:42]([NH:51][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: COC(=O)C(N)C(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (5.49 g; 17.42 mmol) was dissolved in dry tetrahydrofuran (200 ml) and N-methylmorpholine (1.92 ml; 17.42 mmol) was added. The reaction mixture was cooled to −20° C. and stirred 15 min. Isobutyl chloroformate (2.27 ml; 17.42 mmol) was dissolved in dry tetrahydrofuran (3 ml) and added dropwise to the reaction mixture at −20° C. N-methylmorpholine (1.92 ml; 17.42 mmol) and 2-amino-3-oxo-3-phenylpropionic acid methylester (4.0 g; 17.42 mmol) were added and and the mixture was stirred 30 min at −20° C. The reaction mixture was heated to room temperature and the solvent was. removed in vacuo. The residue was dissolved in methylene chloride (200 ml), washed with water (200 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (5×45 cm) using heptane/ethyl acetate/methylene chloride (2:1:1) as eluent to afford 6.19 g of a diastereomeric mixture of 2-((2R)-2-tert-butoxycarbonylamino-3-(2-naphthyl)propionylamino)-3-oxo-3-phenylpropionic acid methylester.
Reaction SMILES: [CH3:1][N:2]([C:9]([C:11]1[C:12]([CH2:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[N:13][S:14][C:15]=1[Si](C)(C)C)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.C(Cl)Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Mn+3]>[CH3:1][N:2]([C:9]([C:11]1[C:12]([CH2:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[N:13][S:14][CH:15]=1)=[O:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(OC)nc(Cc2nsc([Si](C)(C)C)c2C(=O)N(C)c2ccccc2)n1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(OC)nc(Cc2nscc2C(=O)N(C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2.0 g of N-methyl 3-(4,6-dimethoxy-2-pyrimidinylmethyl)-5-trimethylsilyl-4-isothiazolecarboxanilide, 1.5 g of manganese (III) triacetate, 20 ml of acetic acid and 30 ml of methylene dichloride is stirred at RT for 48 hours. The resulting suspension is suction filtered through filter aid and the filter cake washed with water and methylene dichloride. The organic layer is separated, dried and concentrated. The concentrate is flash chromatographed through 300 ml silica gel, 230-400 mesh, using 1 l 70/30 hexane/ethyl acetate, 500 ml 50/50 hexane/ethyl acetate taking 30×50 ml fractions. Fractions 10-15 give a mixture of two components which is heated with boron trifluoride methanol complex (4 drops) in 50 ml of toluene at 80° C. for 2 hrs. The reaction mixture is washed with 30 ml of 15% sodium bicarbonate solution, dried, and concentrated. The concentrate is flash chromatographed through 300 ml silica gel, 230-400 mesh, using 1 l 60/40 hexane/ethyl acetate, 500 ml 40/60 hexane/ethyl acetate and 200 ml ethyl acetate taking 34×50 ml fractions. Fractions 20-23 give N-methyl 3-(4,6-dimethoxy-2-pyrimidinylmethyl)-4-isothiazolecarboxanilide, 0.12 g, mp 92°-93° (Table F, cpd. no. 513). Fractions 24-28 give N-methyl 3-(4,6-dimethoxy-2-pyrimidinylcarbonyl)-4-isothiazolecarboxanilide, 0.3 g, mp 140°-142° C. (Table F, cpd. no. 514).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33]Cl)=[C:28]([CH2:38][CH2:39][CH3:40])[C:27]=1[OH:41])(=[O:25])[CH3:24]>CN(C=O)C>[C:23]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[C:28]([CH2:38][CH2:39][CH3:40])[C:27]=1[OH:41])(=[O:25])[CH3:24]
Reactant: CCCc1c(OCC(O)CCl)ccc(C(C)=O)c1O
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCC(O)COc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)ccc(C(C)=O)c1O
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-7-hydroxycoumarin (5.36 g; 6.02 mole) in dry DMF (30 ml) was treated with 100% sodium hydride (0.48 g; 0.02 mole) and stirred at 100° for about 1 hr. To this was added a solution of 1-(4-Acetyl-3-hydroxy-2-n-propylphenoxy)-3-chloro-2-propanol (7 g) in DMF (2 ml) and the mixture stirred at 100° for an additional 4 hrs. After removal of the solvent in vacuo, water was added and the product extracted into chloroform. Chromatography of the extract on 300 g of silica gel eluting with chloroform afforded the title compound as a white crystalline solid of Rf 0.38. mp (EtOH) 172°-173°. Yield 4.38 g (42%). νmax (mull) 1715; 1630; 1620 cm-1. (DMSO) 9.19 (3H, t, J 7.0 Hz); 8.58 (2H, sextuplet, J. 7.0 Hz); 7.48 (3H, S+ 2 H m); 6.71 (1H sharp exchangeable); 5.80 (5H, S); 4.68 (2H, S), 4.50 (1H, broad exchangeable); 4.13 (1H, S); 3.32 (1H, d, J 9 Hz); 3.12-2.15 (12H, m) 1 low field sharp exchangeable. (Found; C, 69.30; H, 5.80; C30H30O8 requires; C 69.49; H 5.83%).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]([C:10]2[C:11](=[CH:13][C:14](=[CH:16][C:17]=2[OH:18])[OH:15])[OH:12])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C>CO.O>[OH:1][CH:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([C:10]2[C:17](=[CH:16][C:14](=[CH:13][C:11]=2[OH:12])[OH:15])[OH:18])=[O:9])=[CH:19][CH2:20]1
Reactant: O=C(CCc1ccc(O)cc1)c1c(O)cc(O)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(CCC1=CCC(O)C=C1)c1c(O)cc(O)cc1O
Yield: 67.5 %

Procedure:
Phloretin (25 mg) is dissolved in the minimum amount of methanol, diluted with water (3 ml) and treated with a slight excess of NaBH4. After 5 minutes the solution is carefully acidified, with ethyl acetate. The Organic phase is dried over Na2SO4 and evaporated to dryness to give 17 mg of dihydrophloretin as white powder, homogeneous on TLC analysis (silica gel, CHCl3 /MeOH/H2O 70:28:2).