Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=O)=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][NH2:33].C1COCC1>>[CH3:32][NH:33][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23]
Reactant: CN
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and monomethylamine THF solution. Colorless crystals (160 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[N:20][NH:21][C:22]([NH2:24])=[S:23])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)[CH3:2].[Cl:27][CH2:28][CH:29]=O>CN(C)C=O>[ClH:27].[ClH:27].[S:23]1[CH:29]=[CH:28][N:24]=[C:22]1[NH:21][N:20]=[C:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCN(CC)CCn1c2ccccc2c(=NNC(N)=S)c2ccccc21
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c2ccccc2c(=NNc2nccs2)c2ccccc21
Product: Cl

Procedure:
A solution of 6.1 g of 10-[2-(diethylamino)ethyl]-9-acridanone thiosemicarbazone in 100 ml of dimethylformamide is stirred for about 18 hours with 4.3 ml of chloroacetaldehyde (50 percent solution in water). The mixture is subsequently evaporated, the residue is taken up in 50 ml of ethanol, made acid to Congo red with ethanolic hydrochloric acid and the crystals formed are filtered. The crystals are washed successively with ethanol, ether and petroleum ether and there is obtained 10-[2-(diethylamino)ethyl]-9-acridanone (2-thiazolyl)hydrazone dihydrochloride of melting point 214°-216° (decomposition).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8](Br)=[N:7][C:6]([Cl:10])=[CH:5][N:4]=1.[OH2:11].[CH3:12]O>>[NH2:2][C:3]1[C:8]([O:11][CH3:12])=[N:7][C:6]([Cl:10])=[CH:5][N:4]=1
Reactant: O
Reactant: Nc1ncc(Cl)nc1Br
Reactant: CO
Agent: [Na]
Product: COc1nc(Cl)cnc1N
Temperature: 25 °C

Procedure:
Sodium (2.82 g) was dissolved in dry methanol (50 ml) under argon and 2-amino-3-bromo-5-chloropyrazine (1.68 g) was added in small portions with stirring. The stirred solution was heated at reflux under an atmosphere of argon for 4 hours. The solution was allowed to cool to ambient temperature and water (10 ml) was added. Volatile material was removed by evaporation and water (10 ml) was added to the residue. The mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried (MgSO4) and evaporated to give 2-amino-5-chloro-3-methoxypyrazine (1.28 g), m.p. 102°-103° C.; 1H NMR (d6 -DMSO): 3.90 (s, 3 H), 7.53 (s, 1 H); mass spectrum (+ve Cl): 160 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][O:21][CH2:22][CH3:23])[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[C:14]1[CH2:20][O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCn1c(COCC)nc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1cccnc1
Product: CCCCn1c(COCC)nc2c(N)nc3ccc(-c4cccnc4)cc3c21

Procedure:
8-Bromo-1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (8%–10% methanol in CH2Cl2 gradient) followed by recrystallization from isopropanol (3×) and chromatography as above afforded 1-butyl-2-ethoxymethyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 220–222° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:18][CH:19](OC)OC)S(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][C:3]=1[Cl:26].BrC1C=C2C(=CC=1)C=NC=C2>>[Br:1][C:2]1[CH:25]=[C:24]2[C:5](=[CH:4][C:3]=1[Cl:26])[CH:6]=[N:7][CH:18]=[CH:19]2
Reactant: COC(CN(Cc1ccc(Br)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: Brc1ccc2cnccc2c1
Product: Clc1cc2cnccc2cc1Br

Procedure:
Starting from N-(4-Bromo-3-chloro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzene-sulfonamide (8), the title compound was synthesized by the protocol described for 6-Bromo-isoquinoline (3). Rt=1.02 min (Method C). Detected mass: 242.2/244.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccccc3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (25 mg, 0.0595 mmol), phenylboronic acid (8.7 mg, 0.071 mmol), Cs2CO3 (58 mg, 0.18 mmol), and Pd(PPh3)4 (6.9 mg, 0.006 mmol) in DME (1.5 mL) and H2O (0.5 mL) was degassed and refilled with nitrogen (3×). This mixture was then heated at 100° C. using microwave for 30 min. LC-MS showed completion of the reaction. The reaction mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hexane:EtOAc=70:30) to give a brown oil, which was further purified by mass-directed purification to afford the title compound as a brown oil (10.3 mg). 1H NMR (CDCl3, 400 MHz): δ=1.93 (d, J=6.8 Hz, 3H), 6.70 (q, J=6.8 Hz, 1H), 7.10 (dd, J=9.1, 7.8 Hz, 1H), 7.33 (dd, J=9.1, 4.8 Hz, 1H), 7.42-7.55 (m, 5H), 7.67 (s, 1H), 8.12 (s, 1H), 8.18 (s, 1H). MS (ES+): 417.01/418.99 [MH+].
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[C:17]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[N:72][O:73][CH3:74])[C:43]([NH:45][CH:46]2[C:53](=[O:54])[N:52]3[CH:47]2[CH2:48][S:49][C:50]([SH:71])=[C:51]3[C:55]([O:57][CH:58]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=[O:44])[N:41]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[C:17]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=[N:72][O:73][CH3:74])[C:43]([NH:45][C@H:46]2[C:53](=[O:54])[N:52]3[C@@H:47]2[CH2:48][S:49][C:50]([S:71][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:51]3[C:55]([O:57][CH:58]([C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)=[O:56])=[O:44])[N:41]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON=C(C(=O)N[C@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCCN3CCCC3)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
85 mg of N-chloroethyl pyrrolidine hydrochloride, 2 ml of methylene chloride and 210 μl of triethylamine were mixed together and 412 mg of diphenylmethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-mercapto-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate in 3 ml of methylene choride was added. The mixture was refluxed for 3 hours and after cooling to 20° C., the reaction mixture was poured into 10 ml of iced water. The mixture was stirred for 5 minutes, decanted and re-extracted with methylene chloride. The combined organic phases were dried and concentrated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and acetone (1-1). After taking up again in isopropyl ether, 157 mg of syn isomer of racemic cis diphenylmethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[(2-(1-pyrrolidinyl)-ethyl)-thio]-8-oxo-4-thia-1-azabicyclo [4,2,0]oct-2-en-2-carboxylate were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28]O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccc(-c3ccccc3)cc2)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(-c3ccccc3)cc2)on1
Yield: 68.6 %

Procedure:
3-Hydroxy-5-(4-phenylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.22 g, 69%) as a colorless powder.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH2:9]([O:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]1)[CH:10]=[CH2:11].S([O-])([O-])=O.[Na+].[Na+].[OH2:35]>CC(C)=O.C(O)(C)(C)C>[OH:35][CH:10]([CH2:11][OH:5])[CH2:9][O:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@@H:15]([C:25]([O:27][CH3:28])=[O:26])[CH2:14]1
Reactant: O
Reactant: C=CCO[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: COC(=O)[C@H]1C[C@@H](OCC(O)CO)CN1C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
6.16 g (52.6 mmol) of N-methylmorpholine N-oxide (NMO) and 193.7 mg of potassium osmate dihydrate are added successively at room temperature to the solution of 5 g (17.52 mmol) of 1-tert-butyl 2-methyl (2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxylate in 60 ml of water, 25 ml of acetone and 10 ml of tert-butanol, and the mixture is stirred for 48 hours. 6.6 g (52.6 mmol) of sodium sulfite are subsequently added to the reaction mixture, which is stirred at room temperature for a further hour. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 50 ml of water, and the aqueous solution is extracted twice with 20 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 4.7 g of 1-tert-butyl 2-methyl (2R,4R)-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxylate as a yellowish oil; ESI 320. 1.06 g of lithium hydroxide are added to the solution of 4.6 g of this methyl ester in 40 ml of tetrahydrofuran, 10 ml of methanol and 10 ml of water, and the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is subsequently evaporated under reduced pressure, 10 ml of saturated citric acid solution are added to the aqueous solution which remains, and the mixture is extracted three times with 20 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 4.3 g of tert-butyl (2R,4R)-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxylate as a yellow powder; ESI 306. Analogously to Example 7, this acid gives the compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}(2R,4R)-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxamide; ESI 533.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[N:33](C(OC(C)(C)C)=O)[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[CH:26]=2)[CH2:20][C:19]1=[O:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[NH:33][C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[CH:26]=2)[CH2:20][C:19]1=[O:41]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3cc4cnccc4n3C(=O)OC(C)(C)C)C(=O)C2)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2cc3cnccc3[nH]2)CCN1Cc1cc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing 2-[4-(1-tert-Butoxycarbonyl-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxo-piperazin-1-ylmethyl]-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (85 mg, 0.14 mmol) in CH2Cl2 (5 mL) is added TFA (1 mL) at 0° C. and the solution is allowed to slowly warm to ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 45% B over 30 min] to provide 35 mg (36%, two steps) of the title compound as a pale yellow, lyophilized solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[CH:5]=[N:6][CH:7]=1.[NH2:11][C@@:12]1([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:16][CH2:15][O:14][CH2:13]1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C@@:12]2([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[CH2:16][CH2:15][O:14][CH2:13]2)=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(C(=O)O)c1
Reactant: CCCCOC(=O)[C@]1(N)CCOC1
Product: CCCCOC(=O)[C@]1(NC(=O)c2cncc(N)c2)CCOC1
Yield: 96 %

Procedure:
Analogously to Example 1c), 5-aminopyridine-3-carboxylic acid (72.4 mmol) was reacted with n-butyl(S)-3-amino-tetrahydrofuran-3-carboxylate (72.4 mmol). The product was obtained in a yield of 96% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>C(Cl)Cl>[Si:10]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 3-bromobenzyl alcohol (5.00 g, 26.7 mmol) in freshly drieddimethylformamide (10 mL) was added t-butyldimethylsilyl chloride (5.13 g, 33 mmol) and imidazole (4.56 g, 67 mmol). The resulting solution was stirred overnight at ambient temperature. The reaction mixture was poured into water and extracted (3x, 50 mL 1:1 ether:hexanes). The combined organic layers were washed (2x, brine), dried over MgSO4, filtered, and concentrated in vacuo to give a colorless oil which was passed througha short silica gel plug using 10% methylene chloride:hexanes to give pure 3-(t-butyldimethylsilyloxymethyl)bromobenzene (7.9 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.47 (1H, br s), 7.37 (1H, dt, J =7, 1 Hz), 7.16-7.25 (2H, m), 4.24 (2H, s), 0.94 (9H, s), 0.11 (6H, s). MS m/e 318/320(M+NH4)+.
Reaction SMILES: [C:1](=[O:14])(OC1C=CC=CC=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:15][C:16]([NH2:20])([CH3:19])[CH2:17][NH2:18]>CCO>[NH2:20][C:16]([CH3:19])([CH3:15])[CH2:17][NH:18][C:1](=[O:14])[O:2][C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(N)CN
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Solvent: CCO
Product: CC(C)(N)CNC(=O)OC(C)(C)C
Yield: 37 %

Procedure:
Tert-butyl phenyl carbonate (0.421 mL, 2.270 mmol) was added to a solution of 2-methylpropane-1,2-diamine (200 mg, 2.270 mmol) in EtOH (4.5 mL) and the reaction mixture was heated at reflux overnight. The mixture was concentrated and the residue diluted in water. The mixture was acidified with 2N HCl to pH 4 and washed with DCM. The aqueous layer was treated with 1M NaOH (2 mL) and extracted with DCM. The combined organic layers were dried with MgSO4, filtered and concentrated to afford tert-butyl 2-amino-2-methylpropylcarbamate (158 mg, 37% yield) as a colorless oil. MS (apci) m/z=188.9 (M+H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](O)=O)=[CH:4][C:3]=2[O:2]1.B.C1C[O:18]CC1>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:18])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: C1CCOC1
Agent: B
Product: CC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0° C. was added BH3THF (40 ml, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. To work up, THF was evaporated on a rotavap. The residue was treated with water (100 ml) Acidified and extracted with ether (2×100ml). Removal of the solvent under reduced pressure gave 2-(3,4-methylenedioxy)phenyl-1-ethanol as an oil (4.7 g, 98% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]([C:33]2[C:37](=[O:38])[N:36]([CH3:39])[C:35](=[O:40])[C:34]=2[C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43](C(OC(C)(C)C)=O)[CH:42]=2)=[CH:25]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)=O>[NH:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]([C:34]2[C:35](=[O:40])[N:36]([CH3:39])[C:37](=[O:38])[C:33]=2[C:26]2[C:27]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[N:24]([C@@H:6]3[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]3[O:4][C:1](=[O:3])[CH3:2])[CH:25]=2)=[CH:42]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4cn(C(=O)OC(C)(C)C)c5ccccc45)C(=O)N(C)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4c[nH]c5ccccc45)C(=O)N(C)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of Example 16a (0.114 mmol) is dissolved in 20 ml of formic acid. After stirring for 24 hours at ambient temperature, the solution is neutralised by adding, dropwise, triethylamine, and then saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and are then dried over magnesium sulphate and filtered; the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 1/1), the expected product is isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])(C)(C)C>>[C:12]([OH:14])(=[O:13])[C:21]([OH:20])=[O:22].[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cc(Br)c2occc2c1Cl
Product: COC(=O)c1cc(N2CCNCC2)c2occc2c1Cl
Product: O=C(O)C(=O)O

Procedure:
Beginning with 4-chloro-5-methoxycarbonyl-7-bromobenzofuran and 1-tert-butoxycarbonylpiperazine, the title compound was prepared as described.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:41](=[O:42])[C:36]3=[C:37]([Cl:40])[C:38](=[O:39])[C:5]2=[C:6]([C:9]([C:11]([CH3:51])=[CH:12][C@H:13]([CH3:50])[C@@H:14]([OH:49])[C@@H:15]([CH3:48])[CH:16]=[CH:17][C@@H:18]([OH:47])[CH2:19][CH:20]=[C:21]([CH3:46])[C:22]([CH2:24][C@H:25]([OH:45])[C@@H:26]([CH3:44])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[C:32](C)[C:33]([NH:35]3)=[O:34])=[O:23])=[O:10])[C:7]=1[OH:8].C(Cl)(Cl)Cl>CO>[CH3:44][C@@H:26]1[C@@H:25]([OH:45])[CH2:24][C:22](=[O:23])[C:21]([CH3:46])=[CH:20][CH2:19][C@H:18]([OH:47])[CH:17]=[CH:16][C@H:15]([CH3:48])[C@H:14]([OH:49])[C@@H:13]([CH3:50])[CH:12]=[C:11]([CH3:51])[C:9](=[O:10])[C:6]2[C:7]([OH:8])=[C:2]([CH3:1])[CH:3]=[C:4]3[C:41](=[O:42])[C:36](=[C:37]([Cl:40])[C:38]([C:5]=23)=[O:39])[NH:35][C:33](=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: CC1=CC[C@H](O)C=C[C@H](C)[C@H](O)[C@@H](C)C=C(C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC(=O)C(C)=CC=CC=C[C@H](C)[C@@H](O)CC1=O)C3=O
Agent: C/C1=C/C=C\C=C\[C@H](C)[C@@H](O)CC(=O)/C(C)=C/C[C@H](O)/C=C/[C@H](C)[C@H](O)[C@@H](C)/C=C(\C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC1=O)C3=O
Agent: C/C1=C/C[C@H](O)/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C(/C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC(=O)/C=C\C=C/C=C\[C@H](C)[C@@H](O)CC1=O)C3=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1=CC[C@H](O)C=C[C@H](C)[C@H](O)[C@@H](C)C=C(C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC(=O)C=CC=CC=C[C@H](C)[C@@H](O)CC1=O)C3=O

Procedure:
36 g of crude extract were applied to a 3.5×49 cm silica gel column, and eluted successively with chloroform and a chloroform:methanol mixture in which the methanol concentration gradually rose to 5% (final composition 95:5). In this way, 14.6 g of semi-pure compound were obtained, and this was applied to a silica gel (200-300 mesh) column 6×31 cm in size, and was then eluted with a benzene:ethyl acetate mixture gradually increasing the ethyl acetate concentration to 60% (final composition 4:6). This resulted in fraction A in an amount of about 0.19 g and fraction B in an amount of about 1.2 g. For further purification, fraction A was applied to a 1.4×80 cm Sephadex LH 20® column and was eluted with methanol, resulting in 142 mg of a compound which was purified by preparative thin-layer chromatography (silica gel plates of thickness 0.5 mm) in a mixture of chloroform:methanol (95:5). This resulted in 96 mg of a pure compound which was identified as the known antibiotic naphthomycin A. Then a 6×30 cm silica gel H® column (without binder) was charged, as a chromatography column, with fraction B, and elution was carried out with a mixture of chloroform and methanol (96:4). This resulted in 650 mg of a semi-pure substance which was purified by a preparative thin-layer chromatography (silica gel plates 1 mm thick) in a mixture of chloroform and methanol (95:5), and was then recrystallized from a petroleum ether:benzene:ethyl acetate mixture, this resulting in naphthomycin H in an amount of 120 mg.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:6]=[CH2:7])[CH2:4][OH:5].[C:8](OC(C)(C)C)(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]>>[C:8]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH:6]=[CH2:7])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11]
Reactant: C=CC(CO)OC
Reactant: CC(=O)CC(=O)OC(C)(C)C
Product: C=CC(COC(=O)CC(C)=O)OC
Temperature: 134 °C
Reaction time: 7 h

Procedure:
In a 500 mL 3-neck round bottom flask was placed 2-methoxy-3-butene-1-ol (164.46 g, 1.61 mol) and t-butyl acetoacetate (430.20 g, 2.50 mol). Reaction flask was equipped with magnetic stir bar, thermocouple, vigreaux column, and a still head with thermometer. Reaction was heated to 134° C. with stirring for 7 hours, then cooled to room temperature. Product was purified using a short-path distillation apparatus. Distillate was collected until the head temperature exceeded 67° C. NMR of the remaining material indicated the desired product. 1H NMR (CDCl3): d 5.63-5.75 (m, 1H), 5.32-5.40 (m, 2H), 5.06 (s, 1H), 4.10-4.25 (m, 2H), 3.82-3.90 (m, 1H), 3.5 (s, 1H), 3.34 (s, 3H), 2.28 (s, 3H), 1.96 (s, 3H).