Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C@@H]([N:9]2[CH2:13][C@H:12]([C:14]3([NH:18]C(OC(C)(C)C)=O)[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)C)C=CC=CC=1.[NH2:27][C:28]1[C:37]([F:38])=[C:36](F)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44].C(N(CC)CC)C>C(O)C.[C].[Pd].CS(C)=O>[NH2:27][C:28]1[C:37]([F:38])=[C:36]([N:9]2[CH2:13][C@H:12]([C:14]3([NH2:18])[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](F)[C@@H](C2(NC(=O)OC(C)(C)C)CCC2)C1
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(N)CCC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
cis 1-(1-(S)-phenylethyl]-4-(1-tert-butoxycarbonylaminocyclobutyl)-3-fluoropyrrolidine (optical isomer B; 1.13 g, 3.12 mmol) was dissolved in ethanol (20 ml). After adding a 10% palladium-carbon catalyst (moisture content: 55.6%, 1.0 g), the mixture was stirred under a hydrogen atmosphere at 50° C., for 18 hours. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (10 ml), and 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (1.18 g, 3.78 mmol) and triethylamine (5 ml) were added thereto. Then, the mixture was stirred in a nitrogen atmosphere at 140° C. for 4 days. After allowing it to cool, dimethyl sulfoxide was evaporated under reduced pressure and the residue was dissolved in chloroform (50 ml) and washed successively with a 10% aqueous solution of citric acid (50 ml) and a saturated aqueous solution of sodium chloride (100 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was then subjected to flash silica gel column chromatography (eluent:chloroform:methanol=9:1) and the eluate was concentrated under reduced pressure. Under ice cooling, concentrated hydrochloric acid (5 ml) was dropped into the residue followed by stirring at room temperature for 30 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×2) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide. The liquid reaction mixture was washed with chloroform (100 ml) and then its pH value was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (150 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (developed at the bottom layer of chloroform:methanol:water=7:3:1) to obtain the title compound as a crude product. After recrystallizing from ethanol/ether, 157 mg (17%) of the title compound was obtained.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[NH2:5][CH2:6][C@@H:7]([OH:37])[C@@H:8]([NH:18][C:19](=[O:36])[C:20]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:22]([C:23]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[O:24])[CH:21]=1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1.O1C=[CH:41][C:40](C=O)=[CH:39]1.C(N(CC)CC)C>C(O)C.[Pd]>[F:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([F:17])[CH:13]=1)[CH2:9][C@H:8]([NH:18][C:19](=[O:36])[C:20]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:22]([C:23]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[O:24])[CH:21]=1)[C@H:7]([OH:37])[CH2:6][NH:5][CH2:41][C:40]1[O:4][CH:1]=[CH:2][CH:39]=1
Reactant: CC(=O)O
Reactant: O=Cc1ccoc1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2ccco2)c1
Temperature: 22.5 °C
Reaction time: 0.17 h

Procedure:
N1-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N3,N3-dipropylisophthalamide acetic acid salt (XVI, EXAMPLE 168, 76 mg, 0.146 mmol) is dissolved in absolute ethanol (2 mL). 3-Furaldehyde (20 microL, 0.231 mmol) and triethylamine (30 microL, 0.215 mmol) are added via syringe, with stirring at 20-25 degrees C. After 10 minutes, palladium on carbon 122 mg, 5 weight %) is added and the mixture placed under a hydrogen atmosphere (50 psi) and shaken for 20 minutes. The resulting mixture is then filtered through diatomaceous earth, with ethanol washings. The filtrate is purified by flash chromatography (2-10% methanol/methylene chloride) to give purified title compound, MS (MH+)=542.2.
Reaction SMILES: [CH2:1]([P:9]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[OH:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([P:9]([Cl:23])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=P(O)(CCc1ccccc1)CCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=P(Cl)(CCc1ccccc1)CCc1ccccc1

Procedure:
Diphenethylphosphinic acid (1.67 g, 6.1 m mole) was dissolved in carbon tetrachloride (5 ml), and sulfuryl chloride (1.46 g, 10.8 m mole) was added thereto, and the mixture was heated while refluxing for 2 hours. It was confirmed that the starting material did not remain by tracement of the NMR spectrum. The solvent and excess sulfuryl chloride were distilled off under reduced pressure to obtain an oily diphenethylphosphinylchloride, which was supplied for the following reaction.
Reaction SMILES: [CH2:1]([O:3][CH:4]([PH:8](=[O:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[F:22][C:23](=[CH:29][CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:5][CH2:6][CH3:7])[P:8]([CH:29]([CH3:30])[CH:23]([F:22])[C:24]([O:26][CH2:27][CH3:28])=[O:25])([O:9][CH2:10][CH3:11])=[O:12])[CH3:2]
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: CC=C(F)C(=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)C(C)P(=O)(OCC)C(OCC)OCC
Temperature: 25 °C
Yield: 116.3 %

Procedure:
A mixture of ethyl (diethoxymethyl)phosphinate (21.7.0 g, 110 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (23.3 mL, 110 mmol) was heated to reflux for 2 h under an argon atmosphere. The mixture was cooled to room temperature and a diastereomeric mixture ethyl 2-fluorobut-2-enoate (14.6 g, 110 mmol) was added. The reagents were heated to 80° C. for one day and 120° C. for 2 hours under an argon atmosphere. The mixture was cooled to room temperature and another portion of trimethylsilyl activated ethyl (diethoxymethyl)phosphinate was added (this had been prepared from ethyl (diethoxymethyl)phosphinate (21.7.0 g, 110 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (23.3 mL, 110 mmol) in the same way as above). The mixture was heated to 100° C. for three days and still another portion of trimethylsilyl activated ethyl (diethoxymethyl)phosphinate was added. The mixture was heated to 100° C. for three days under an argon atmosphere, cooled to room temperature and then diluted with ethyl acetate (300 mL). The solution was washed with 1 N HCl (2×200 mL) and saturated sodium chloride. The organic layer was dried over MgSO4, filtered, and evaporated to give 42.0 g of a yellow oil. The residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride and then with 98:2 methylene chloride/methanol. The appropriate fractions were combined and evaporated to give 3.6 g (10%) of ethyl 3-[(diethoxymethyl)(ethoxy)phosphoryl)]-2-fluorobutanoate as a clear oil. 1H NMR (400 MHz, CDCl3) δ 4.9-5.6 (m, 1H), 4.7-4.8 (m, 1H), 4.2-4.4 (m, 4H), 3.6-4.0 (m, 4H), 2.6-2.9 (m, 1H), 1.2-1.4 (m, 12H).
Reaction SMILES: I[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>C(#N)C.[Hg]>[CH:7]([C:5]1[S:6][C:2]([C:13]2[S:9][C:10]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: c1csc(-c2cccs2)c1
Reactant: O=Cc1ccc(I)s1
Agent: [Hg]
Solvent: CC#N
Product: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1

Procedure:
1 g of 5-iodo-2-thiophenecarboxaldehyde was dissolved in 200 ml of acetonitrile. 0.7 g of bithiophene was added into the solution under nitrogen gas atmosphere for 1 hour and irradiated under 100 W mercury-vapor lamp light for 12 hours. The solution was monitored by thin layer chromatography. At this stage, about 60% product was generated. The acetonitrile was removed from the reaction solution under reduced pressure and CH2Cl2 was added for extraction. After the extract was filtered through silica gel layer and separated by column chromatography, starting material was recovered from the eluate of ethyl acetate/n-hexane 1/9 fraction and 5-formyl-2,2':5',2"-terthiophene was obtained from the eluate of ethyl acetate/n-hexane 3/7 fraction respectively.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-:7].[Na+]>O>[C:1]([O:6][C:3](=[O:7])[C:2]([CH3:4])=[CH2:1])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: [OH-]
Reactant: C=C(C)C(=O)O
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OC(=O)C(=C)C

Procedure:
The 81A product (11.51 gm) was allowed to react under the conditions of Example 1 with 5.28 gm XSA, 9.99 gm methacrylic acid, 2.78 gm AMPS, and 44.50 gm water. After reaction, 6.94 grams of water was added along with NaOH to adjust pH to 4.4 (referred to below as 81B). The solution contained 29% solids.
Reaction SMILES: N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:19]([N:21]([CH2:25][CH:26]=[CH2:27])[CH2:22][CH:23]=[CH2:24])=[O:20].[SH2:28]>CO>[CH:19]([N:21]1[CH2:25][CH:26]([CH3:27])[S:28][CH:23]([CH3:24])[CH2:22]1)=[O:20]
Reactant: C=CCN(C=O)CC=C
Reactant: S
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CO
Product: CC1CN(C=O)CC(C)S1
Reaction time: 48 h

Procedure:
Piperidine (10 ml) and 10 ml of a 40% solution of benzyltrimethylammoniumhydroxide in methanol were added to a solution of N-formyl-diallylamine (55 g) in methanol (200 ml). Hydrogen sulfide (50 g) was introduced into the resulting solution, and unreacted hydrogen sulfide was kept at reflux for 7 hours by means of "cold finger". The mixture was left at room temperature for 48 hours, flushed with nitrogen, diluted with ether, and washed with water. The organic phase was dried, and the solvent evaporated in vacuo. Distillation of the residue gave the title compound with boiling point 145° C./15 mmHg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+]([O-])=O)=[C:6]([CH:11](C2C=CC=CC=2)[OH:12])[C:7]=1[N+:8]([O-:10])=[O:9].ClC1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(C(C2C=CC=CC=2)O)C=1.[CH3:43][NH:44][CH3:45]>CO>[CH3:43][N:44]([CH3:45])[C:4]1[CH:3]=[CH:2][C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][OH:12])[CH:5]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1C(O)c1ccccc1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(C(O)c2ccccc2)cc1Cl
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])c(CO)c1

Procedure:
(5-Chloro-2,6-dinitro-phenyl)-phenyl-methanol (13) (0.5 g, 1.90 mmol) or (5-chloro-2,4-dinitro-phenyl)-phenyl-methanol (14) (0.5 g, 2.67 mmol) were treated with 2M solution of dimethylamine in methanol (6 mL) and the solution was heated in a microwave reactor (CEM Focused Microwave™ Synthesis System Model Discover) at 50-55° C. for 15 minutes. The solvent was removed in vacuo and each residue was coevaporated with dichloromethane (2×10 mL) and applied onto a column of silicagel. The column was eluted with dichloromethane/ethanol (49:1) to give compounds 17 and 18.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH2:13]O)[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:40]I>CCOCC.C(#N)C>[CH2:1]([N:8]1[C@H:12]([CH2:13][I:40])[CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@@H](CO)N1Cc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C1CC[C@@H](CI)N1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13-1 (18.5 g, 90.1 mmol), triphenylphosphine (40.1 g, 153 mmol), and imidazole (11.03 g, 162 mmol) in 225 mnL of acetonitrile and 150 mL of ether at 0° C. was added iodine (34.3 g, 135 mmol) in 5 portions over 5 minutes. After 10 minutes, the reaction was heated to 50° C., and a stream of argon passed over the reaction to purge the evaporating ether. After an additional 30 minutes, the mixture was diluted with ether, the organic layer washed with NaHCO3 (sat.) and brine, dried over K2CO3, and the solvent evaporated. Flash chromatography of the residue (silica, 7-15% EtOAc/CHCl3) gave 13-2 as a yellow oil.
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[N:16]1[CH2:21][CH2:20][CH2:19][C@H:18](N)[CH2:17]1)([O-:5])=[O:4].C=O.[C:25](O)(=O)C.[C:29]([BH3-])#[N:30].[Na+]>CO>[CH3:25][N:30]([CH3:29])[C@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:6]=2[N+:3]([O-:5])=[O:4])[CH2:17]1
Reactant: [BH3-]C#N
Reactant: N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reactant: CC(=O)O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a yellow solution of (S)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine dihydrochloride (13.39 g, 37 mmol) in 123 mL MeOH under nitrogen at 0° C. was added formaldehyde (37% solution) (14 ml, 185 mmol), Acetic acid (11 ml, 185 mmol), and sodium cyanoborohydride (4.6 g, 74 mmol) in portions over 5 min. The cloudy mixture was warmed to ambient temperature. After 10 min, the reaction became quite hot and was cooled with an ice bath. After 1.5 h, the reaction was complete by LCMS. The solvent was removed in vacuo, and the flask cooled to 0° C. Water was added, and the mixture was basified with 1N NaOH, and 6N NaOH. The mixture was extracted with 1×200 mL EtOAc, 1×100 mL EtOAc, and the combined organics were dried over anhydrous Na2SO4 and concentrated in vacuo to give (S)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine as an orange oil. MS m/z=318 [M+H]+. Calc'd for C14H18F3N3O2: 317.
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)OC1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](I)=[C:32]([F:37])[CH:31]=1.C(=O)([O-])O.[Na+].O>COCCOC.C(OC(C)C)(C)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:17][O:18][C:19]([CH3:23])([CH3:22])[O:20][CH2:21]3)=[CH:12][CH:13]=2)=[C:32]([F:37])[CH:31]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(=O)NC1(CCc2ccc(B3OCC(C)(C)CO3)cc2)COC(C)(C)OC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: COCCOC
Solvent: O
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 62.3 %

Procedure:
A mixed solution of N-(5-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (7.33 g) of Reference Example 6, 1-bromo-3-fluoro-4-iodobenzene (5.95 g), sodium hydrogen carbonate (9.48 g) and tetrakistriphenylphosphine palladium (434 mg) in 1,2-dimethoxyethane (120 mL)-water (40 mL) was heated under reflux for 8 hr. 1-Bromo-3-fluoro-4-iodobenzene (2.83 g) and tetrakistriphenylphosphine palladium (217 mg) were added to the reaction mixture, and the mixture was further stirred at 100° C. for 15 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, and the obtained crude crystals were suspended in diisopropyl ether and collected by filtration to give the title compound (5.28 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:23]2[O:22][C:9]3[C:10](=[O:21])[N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:14](=[O:15])[C@@H:13]([N:11]2[CH2:12][C:8]3[CH2:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:23]=4[O:22][C:9]=3[C:10]2=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:29][CH:28]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Reactant: COC(=O)c1ccc(N)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4c(Cl)cccc4C3)C2=O)nc1
Yield: 33.1 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (100 mg, 0.27 mmol), commercially available 6-aminonicotinic acid methylester (109 mg, 0.71 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (125 mg, 0.66 mmol), and N-hydroxybenzotriazole (HOBt) (88 mg, 0.66 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoyl-amino]-nicotinic acid methyl ester (42 mg, 15%), as a white solid. 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.88 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.08-7.16 (m, 1H), 5.10 (d, J=7.3 Hz, 1H), 4.42 (d, J=19.1 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.86 (s, 3H), 3.83 (br. s., 2H), 1.76-2.02 (m, 1H), 1.69 (t, J=9.3 Hz, 1H), 1.48 (br. s., 1H), 0.87-0.99 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[CH:6]C(O)=O.C([N:16]([CH2:19]C)CC)C.ClC(OCC)=[O:23].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:19](=[O:23])[NH:16][CH:6]=[CH:5]2
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(C=CC(=O)O)cc1F
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2c(=O)[nH]ccc2cc1F
Temperature: 150 °C
Yield: 41.7 %

Procedure:
To a solution of 10.0 g of 3-fluoro-4-methyl-cinnamic acid in 80 ml acetone were subsequently added at 0° C. 6.74 g triethylamine in 10 ml acetone followed by 7.83 g ethyl chloroformate. After stirring for 2 h at 0 to 5° C. a solution of 4.0 g sodium azide in 9.5 ml water was added. After stirring for 1 additional h the reaction mixture was poured onto 200 ml ice water and extracted twice with chloroform. The organic phase was dried over magnesium sulfate, 40 ml diphenylether were added and the chloroform was cautiously removed in vacuo. The residue was then added dropwise into 50 ml of diphenylether which had been preheated to 245° C. After complete addition it was stirred for 1 further h at 230-250° C. After cooling down to 150° C. the reaction mixture was poured into 270 ml heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 4.1 g 6-fluoro-7-methyl-2H-isoquinolin-1-one (12) were obtained. Rt=1.25 min (Method B). Detected mass: 178.1 (M+H+).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][CH2:21][OH:22]>ClCCl>[OH:22][CH2:21][CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Reactant: OCCS
Solvent: ClCCl
Product: O=C1c2c(O)cccc2C(SCCO)c2cccc(O)c21
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (100 mg) was dissolved in dichloromethane (7 ml) and 2-mercaptoethanol (0.03 ml) was added. The solution was stirred at room temperature for 7 hours, during which time the light brown solution became pale green. Removal of the solvent and recrystallisation of the residue from a hexane/chloroform mixture (5:1) gave 10-(2-hydroxyethylthio)-1,8-dihydroxy-9-anthrone (89 mg, 90%) as pale yellow needles, melting point 146°-147° C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH3:21][O:22][CH2:23]C(Cl)=O.[N:27]1[C:36]2[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11](=[O:13])[CH2:23][O:22][CH3:21])[C@H:8]([C:18]([NH:37][C:33]2[CH:32]=[C:31]3[C:36](=[CH:35][CH:34]=2)[N:27]=[CH:28][CH:29]=[CH:30]3)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: Nc1ccc2ncccc2c1
Reactant: COCC(=O)Cl
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1C[C@@H](C(=O)Nc2ccc3ncccc3c2)N(C(=O)COC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and 6-quinolinamine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=383.0.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:15][CH2:16][O:17][CH3:18])[CH:3]=1.[OH-].[K+]>CO.O>[OH:1][C:2]1[C:11]([CH:12]([CH3:13])[CH3:14])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:15][CH2:16][O:17][CH3:18])[CH:3]=1
Reactant: COCOc1cc(O)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1cc(O)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 25 %

Procedure:
The crude methyl 4-hydroxy-5-isopropyl-2-(methoxymethyloxy)benzoate was dissolved in methanol (20 ml) and water (8 ml), aqueous potassium hydroxide (50% w/v, 5 ml) was added and the mixture was stirred and held at reflux for 16 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (30 ml). The organic material was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were evaporated in vacuo to afford a yellow oil that was subjected to column chromatography on a Strata-NH2 cartridge. Elution with 2M ammonia in methanol afforded crude 4-hydroxy-5-isopropyl-2-(methoxymethyloxy)benzoic acid (180 mg, 25%) as a pale grey solid that was used without further purification. MS: [M+Na]+ 263.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])=[O:3].[CH3:13][Mg+].[Br-]>C1COCC1>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:2]([OH:3])([CH3:13])[CH3:1]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2-fluoro-4-methoxyacetophenone (4.45 g, 26.5 mmol) in THF (50 mL) at 0° C., a solution of 2.4 M MeMgBr (11.6 mL, 27.8 mmol) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution. The organic layer was extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers were washed with brine and dried over sodium sulfate. The title compound was obtained as an oil after flash column using EtOAc:hexane=2:8 as the elute.