Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[CH:14]=[CH:13][CH:12]=[N:11][C:5]=1[NH:6]2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:15]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2[CH:14]=[CH:13][CH:12]=[N:11][C:5]=2[NH:6]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccc2[nH]c3ncccc3c12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(-c2cccc3[nH]c4ncccc4c23)cc1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
Compound 4 (20 mg, 0.081 mmol) was mixed with phenylboronic acid (20 mg, 0.16 mmol) and Tetrakis Pd(0) catalyst (19 mg, 0.016 mmol) in a solution comprising dioxane (3 ml) and a saturated K2CO3 solution (1 ml). The mixture was heated in a microwave reactor at 150° C. for 20 minutes. Purification by HPLC afforded the title compound as a tan solid (4 mg, 22%). 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1 H) 8.10 (d, J=7.84 Hz, 1 H) 7.67 (m, 2 H), 7.60 (m, 5 H) 7.27 (m, 2 H). [M+H] calc'd for C17H12N2, 245; found 245.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[CH:4][N:3]=[CH:2]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C.C(OCC)(=O)C>[CH:13](=[N:8]/[C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[C:5]1[NH:1][CH:2]=[N:3][CH:4]=1)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1-c1cnc[nH]1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C(=N/c1ccccc1-c1cnc[nH]1)\c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
2-(1H-imidazol-5-yl)aniline 965 mg, 0.410 mmol) was dissolved in acetic acid (2 mL) and benzaldehyde (43 mg, 0.410 mmol) was added. The reaction was stirred for 1 h at room temperature, diluted with 30 mL ethyl acetate, and extracted with 5% HCl (56 mL from 50 mL water+6 mL 12N HCl). The aqueous layer was basified with K2CO3 (add solid portionwise until PH=7), then extracted with ethyl acetate (30 mL×2). The organic layer was evaporated under reduced pressure and the residue was separated by column chromatography to afford the desired product (9 mg, 0.036 mmol, 9%). 1H NMR (MeOH-d4): 7.11-7.25 (m, 3H), 7.41-7.48 (m, 2H), 7.61-7.67 (m, 2H), 7.78 (s, 1H), 8.32 (s, 1H), 8.39 (s, 1H), 8.83 (s, 1H).
Reaction SMILES: [C:1]1([S:11]([O-:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[C:1]1([S:11]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]([CH3:25])[C:20]4[CH2:26][CH:27]5[NH:31][CH:30]([C:19]=4[C:18]=3[C:17]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1cccc2ccccc12
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc5ccccc45)ccc31)C1CCC(C2)N1
Yield: 26 %

Procedure:
Intermediate 23 was coupled with the product of Example 27, step B following the procedure of Example 27, Step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(1-napthyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (120 mg, 26%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.48 (dd, J=7.5, 1.2 Hz, 1H), 8.20 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.86 (dd, J=8.6, 1.5 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.40-7.52 (m, 4H), 5.25 (br s, 1H), 4.69 (br s, 1H), 3.59 (s, 3H), 3.36 (br s, 1H), 2.45 (d, J=6.0 Hz, 1H), 2.14-2.38 (m, 2H), 1.87-1.96 (m, 1H), 1.59-1.67 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][C:21]([OH:23])=[O:22].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 50 ml of water was suspended 2.5 g of N-(benzyloxycarbonyloxy)succinimide, and the suspension was stirred for 1 hour at room temperature. To this suspension was added 20 ml of an aqueous solution of 0.75 g of glycine and 1.4 ml of triethylamine, and the reaction mixture was stirred for 12 hours as it was, but the desired product, benzyloxycarbonylglycine, could not be obtained.
Reaction SMILES: [N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[SH:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29].C(Cl)CCl>CN(C)C=O>[N:1]1([C:21]([CH3:23])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([NH:13][CH2:14][C:15]([S:24][NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:17])=[O:12])[CH2:7][CH:8]([CH3:9])[CH3:10])=[O:4]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NS
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NSC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of Ac-Pro-Leu-Gly-OH (0.7 g, 2.1 mmol), HS-Leu-Leu-Gly-OC2H5 (0.6 g, 1.7 mmol) and HBT (0.26 g, 1.7 mmol) in 15 ml dimethylformamide was added EDC (0.4 g, 2.1 mmol). The solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between salt water and ethyl acetate. The ethyl acetate layer was washed consecutively with dilute sodium bicarbonate in salt (NaCl) water, dilute hydrochloric acid in salt water, salt water, 1.0 mM cupric sulfate in salt water (to remove any mercapto products) and finally salt water. The ethyl acetate was dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate concentrated in vacuo, yielding 0.8 g (73%) glassy residue of crude thiopeptolide product. A 100 mg sample of this crude product was purified by low pressure C18 column chromatography. The purified thiopeptolide, had an acceptable amino acid analysis, a consistent mass spectrum and a single peak on HPLC analysis. Anal. Calcd. for
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C:8](=O)[CH2:7]1)=[O:5])[CH3:2].O[C@@H:13](C1C=CC=CC=1)[CH2:14][N:15]1C2(CCN(C)CC2)CCN2C(=O)C=C(C3C=CN=CN=3)N=C12>>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C:8](=[CH:13][C:14]#[N:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: CN1CCC2(CC1)CCn1c(nc(-c3ccncn3)cc1=O)N2C[C@@H](O)c1ccccc1
Product: CCOC(=O)N1CCC(=CC#N)C1

Procedure:
The product was obtained by analogy with the method described in example 1.1 (step1.1)and using 3-oxo-pyrrolidine-1-carboxylic acid ethyl ester prepared according to Visconti, M et al. Helvetica Chimica Acta 1967, 50 (5) 1289-93.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:26]Cl>CO>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:26])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: ClI
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 5.22 mmol) in methanol (70 mL) was treated with CaCO3 (1.06 g, 10.44 mmol) followed by a solution of ICl (1.70 g, 10.44 mmol) in methanol (10 mL), and stirred overnight at 20 C. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), extracted twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.54 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.55 (m, 1 H), 6.57 (m, 1 H), 3.86 (s, 3 H), 3.80 (m, 1 H), 3.60-3.30 (m, 2 H), 3.20-2.80 (m, 4 H), 1.30 (m, 3 H). MS calculated for C14H15F3INO2+H: 414, observed: 414.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH:5]([CH3:6])[CH2:4][CH2:3][CH2:2]1.[OH-:9].[K+].Cl>C(O)C.O>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: CC1CCCC(=O)O1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCO
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 82.8 %

Procedure:
To a solution of 12.0 g of ε-hexanolactone in 20 ml of ethanol was added a solution of 11.7 g of potassium hydroxide in 20 ml of water under ice-cooling and the reaction mixture was stirred for 2.5 hours at 40° C. After reaction, the reaction mixture was adjusted to pH 9 by adding 1N-HCl solution and washed with ethyl acetate (twice). The aqueous layer was concentrated under reduced pressure and the residue was adjusted to pH 1 by adding 1N-HCl solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give 11.5 g of 6-hydroxyhexanoic acid. A mixture of 1 g of 6-hydroxyhexanoic acid obtained above, 0.72 mg of sodium bicarbonate in 20 ml of water was stirred for 15 minutes. After reaction, the solvent was removed and the resulting residue was washed with acetonitrile to give 1.24 g of sodibm 6-hydroxyhexanoic acid. Then, 276 mg of this compound was dissolved in 2.7 ml of dimethylformamide and to this solution was added 161 mg of methoxymethyl chloride and the reaction mixture was stirred for 1.5 hours at room temperature. After adding 10 ml of ethyl acetate to the reaction mixture, the organic layer was washed with saline, saturated sodium bicarbonate aqueous solution and saline respectively and dried over magnesium sulfate. The solvent was removed to give 190 mg (59%) of methoxymethyl 6-hydroxyhexanoate [Compound (15)].
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[C@H:13]([C:25]([OH:27])=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][O:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:35]([O:34][C:33]([NH:32][CH2:31][CH2:30][O:29][NH:28][C:25]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]([NH:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][N:14]1[C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])=[O:17])=[O:27])=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: C[Si](C)(C)CCOC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
(2S,5R)-5-(Benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylic acid (601 mg, 1.52 mmol) described in Example 101 and tert-butyl 2-(aminooxy)ethylcarbamate (303 mg, 1.72 mmol) of Reference Example 9 were dissolved in N,N-dimethylformamide (5.8 mL), to which was added 1-hydroxybenzotriazole.monohydrate (264 mg), followed by ice cooling. To this was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), a temperature was elevated to room temperature, followed by reaction for 5 h. Water was added to the reaction mixture and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, the organic layer was dehydrated over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 450 mg of the title compound (yield 54%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[NH:10][C:9]1=[O:18].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>CN(C)C=O.O>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]([CH2:22][CH:19]2[CH2:21][CH2:20]2)[C:9]1=[O:18]
Reactant: BrCC1CC1
Reactant: Cn1c(=O)[nH]c2sccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2ccsc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium carbonate (1.0 g) was added to a mixture of 3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg; J. Chem. Soc. Perkin Trans.1; 1980; 1853) and cyclopropylmethyl bromide (1.0 ml) in dry dimethylformamide (15 ml). The solution was stirred at room temperature for 20 hours and was then diluted with water and extracted thrice with diethyl ether. The combined organic extracts were washed with brine, then dried, filtered and evaporated. The residue was purified by column chromatography over silica, eluting with ethyl acetate: isohexane (1:4) to give the subtitle compound (180 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>C(Cl)Cl>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:21]
Reactant: CCOC(=O)c1csc(CO)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of ethyl 2-(hydroxymethyl)-thiazole-4-carboxylate 33 (38.4 g) and pyridine (41 mL) in 100 mL of CH2Cl2 is slowly added 2,2,2-trichloroethyl chloroformate (32 mL, 0.23 mol) at 0° C. After the resulting mixture is stirred for 30 minutes, the reaction is quenched by the addition of 10% aq NaHCO3. The organic layer is separated, and the aqueous layer is extracted with CH2Cl2. The combined organic extracts are washed with 2 N HCl, 10% aq NaHCO3, and brine, dried (Na2SO4), and concentrated. The residue is then recrystallized in ethanol (50 mL) to yield a light yellow solid (35 g). The mother liquor is concentrated and chromatographed to afford an additional amount (35 g) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[C:10](O)(=[O:13])[CH2:11][CH3:12]>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: CCC(=O)O
Reactant: Oc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A mixture of 2,6-dichlorophenol (10.10 g, 61.96 mmol) and propionic acid (3.34 mL, 62.58 mmol) in trifluoromethanesulfonic acid (50 g) was heated to 80° C. for 24 h. The reaction was cooled to ambient temperature, poured onto ice and extracted with chloroform (3×). The combined organic layer was washed with aqueous bicarbonate and brine, dried, and concentrated to give 8.90 g (66%) of 2,6-dichloro-4-propionylphenol as a tan solid which had: mp 50-52° C.; NMR δ 7.89 (s, 2 H), 6.29 (s, 1 H), 2.91 (q, J=7 Hz, 2 H), 1.20 (t, J=7 Hz, 3 H). This material was used without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:16][OH:17])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([NH2:15])[CH:7]=1)=[O:4].[C:18]([C:21]1[C:22](=[O:32])[O:23][C:24]([OH:31])=[C:25]([C:28](=O)[CH3:29])[C:26]=1[OH:27])(=[O:20])[CH3:19]>CO>[C:18]([C:21]1[C:22](=[O:32])[O:23][C:24](=[O:31])[C:25](=[C:28]([NH:15][C:8]2[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH2:16][OH:17])[OH:1])[CH:7]=2)[CH3:29])[C:26]=1[OH:27])(=[O:20])[CH3:19]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1cc(NC(=O)C(O)CO)cc([N+](=O)[O-])c1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2cc(NC(=O)C(O)CO)cc([N+](=O)[O-])c2)C(=O)OC1=O
Yield: 42.9 %

Procedure:
A mixture of 785 mg (3.3 mmole) of N-(2,3-dihydroxypropionyl)-3-amino-5-nitroaniline and 690 mg (3.3 mmole) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 30 ml of methanol was heated under reflux for 30 minutes. After cooling, the crystalline product was filtered and dried in vacuum to give 616 mg of 5-acetyl-4-hydroxy-3-[1-(3-glyceroylamino-5-nitrophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH:22]([CH3:45])[CH:23]([C:25]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[C:31]([F:34])[CH:32]=2)[N:27](S(C2C=CC=CC=2)(=O)=O)[CH:26]=1)O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.O1CCCC1>[CH2:15]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:22]([CH3:45])[CH2:23][C:25]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[C:31]([F:34])[CH:32]=2)[NH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Lithium aluminum hydride (LAH) (0.7 g, 18 mmol) is added portionwise to a dioxane/tetrahydrofuran (90 ml/10 ml) solution of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol (1.9 g, 3.3 mmol) under N2 at 0° C. After the addition is complete, the reaction is allowed to warm to room temperature, then is refluxed for 1 hour. The reaction is quenched with H2O and 15% aqueous NaOH, filtered, and the filtrate is diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.2 g of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(S)-methyl-ethyl]-amine (86%).
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[Cl-].[C:19]([O:30][CH3:31])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:31][O:30][C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:10]=[C:2]([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CCCCC(=N)OCC
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(=NC(=O)c1ccc(C(=O)OC)cc1)OCC
Temperature: 25 °C
Reaction time: 19 h
Yield: 12.1 %

Procedure:
To a solution of ethyl pentanimidate hydrochloride (9 g, 54 mmol) and triethyl amine (17 mL, 120 mmol) in toluene (110 mL) at 0° C. was added, over 20 minutes, a solution of terephthalic acid, monomethyl ester chloride (10.8 g, 54 mmol) in toluene (21 mL). After stirring at ambient temperature for 19 hours, the reaction was filtered and the solids were rinsed with toluene (200 mL). The combined filtrates were concentrated in vacuo. Flash chromatography (silica gel, CH2Cl2) of a portion of this material afforded the title compound (1.9 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[C:11]([F:21])([F:20])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([C:36]2[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=2[C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[F:20][C:11]1([F:21])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (200 mg) and 5 ml of pyridine were dissolved in 10 ml of methylene chloride, and 10 ml of a methylene chloride solution containing the o-phenylbenzoic acid chloride obtained above was added dropwise under ice-cooling. After 1 hour of stirring at room temperature, the solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution, 1N hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution in that order. After drying on anhydrous magnesium sulfate and subsequent evaporation of the solvent under a reduced pressure, the resulting residue was applied to column chromatography, which was eluted with a mixed solvent of ethyl acetate and hexane (2:3, v/v) to obtain 283 mg of 4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. This product was recrystallized from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:8]1[S:12][CH:11]([O:13][C:14]([CH2:16]Cl)=[O:15])[CH2:10][S:9]1)=[O:6])[CH3:3].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>O1CCCC1>[CH3:25][CH2:24][N:26]([CH2:16][C:14]([O:13][CH:11]1[S:12][C:8](=[C:7]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:6])[S:9][CH2:10]1)=[O:15])[CH2:27][CH3:28]
Reactant: CC(C)OC(=O)C(C(=O)OC(C)C)=C1SCC(OC(=O)CCl)S1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)OC1CSC(=C(C(=O)OC(C)C)C(=O)OC(C)C)S1
Yield: 74 %

Procedure:
3.8 Grams (0.01 mole) of the diisopropyl ester of 4-chloroacetoxy-1,3-dithiolan-2-ylidene malonic acid obtained in Example 2 was dissolved in 50 ml of tetrahydrofuran. To the resulting solution was added 1.5 g (0.02 mole) of diethylamine, and the resulting mixture was refluxed for 3 hours. After the reaction, the formed diethylamine hydrochloride was removed by filtration, and then the tetrahydrofuran was removed by distillation. The residue was washed with water and then extracted with 1 N--HCl. The extract was neutralized with a dilute aqueous sodium hydroxide solution to form an oily substance. This oily substance was extracted with ether, and the ether extract was washed with water, dried and the freed from the ether by distillation, whereby 3.5 g of crude crystals of the desired product were obtained. Subsequently, the crude crystals were recrystallized from n-hexane to obtain 3.1 g of white crystals, m.p. 70.5°-71° C., yield 74 %.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1
Reactant: COC(=O)CCCCCCCNc1ccc(OC)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 5 h

Procedure:
12 g (43 mmol) of 8-(4-methoxyphenylamino)-caprylic acid methyl ester are dissolved in 400 cc. of ether. 5.1 g (50 mmol) of triethylamine are added thereto. 7.3 g (43 mmol) of 4-methoxybenzoic acid chloride are added dropwise to the mixture with stirring and cooling with ice. After the addition, stirring is continued at 25° C. for 5 hours. The separated triethylamine-hydrochloride is filtered off with suction and the ethereal phase is washed in sequence with water, 5% bicarbonate solution, water, 2 n hydrochloric acid and water is dried over Na2SO4, and the solvent is distilled off. The crude product is used in the next step without any further purification.