Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=O)[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.Cl.[NH2:40][C@H:41]([C:46]([CH2:48][F:49])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44]>C1COCC1.CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:40][C@H:41]([C:46]([CH2:48][F:49])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)CF
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)CF
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a solution of Boc-LeuCH2F (1.53 g, 6.19 mmol) in ether (30 mL) was added a saturated solution of HCl in ether (20 mL). The mixture was stirred vigorously; a precipitate formed within 15 minutes. After 1 hour, the mixture was filtered, the solids were washed with ether (2×30 mL) and were then pumped dry overnight; a second crop was obtained from the filtrate, giving 0.60 g (54%) of LeuCH2F hydrochloride. Boc-Phe-Gly-LeuOH (synthesized in several steps via mixed anhydride coupling of the appropriate amino acid benzyl esters and subsequent hydrogenolyses, 0.762 g, 1.69 mmol) was dissolved in THF (10 mL), and was cooled to -20° C. NMM (0.186 mL, 1.69 mmol) was added, followed by IBCF (0.219 mL, 1.69 mmol). After 5 minutes, HCl.LeuCH2F (0.31 g, 1.69 mmol) was dissolved in DMF (2 mL), to which solution was added NMM (0.186 mL, 1.69 mmol). This mixture was swirled for approximately 15 seconds and was added to the mixed anhydride solution. After 45 minutes, the reaction was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×30 mL), the combined organics were washed with saturated aqueous NaHCO3 (30 mL), brine (20 mL), dried over MgSO4, filtered, and evaporated. The thick oil was then dissolved in 1:1 ether/CH2Cl2 (20 mL), and hexane (50 mL) was added. After one day, the supernatant was decanted from the impure product and was evaporated to dryness, yielding 0.14 g of Boc-Phe-Gly-Leu-LeuCH2F.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.CS(C)=[O:41]>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH2:29][OH:41])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:4][CH:3]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reactant: CS(C)=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)CO)cc3)ncnc2OCCOc2ncc(Br)cn2)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 mm Erlenmeyer flask containing 50 mm of AS-7H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of six 300 mm Erlenmeyer flask containing 50 mm of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-[6-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-(4-methylphenyl)-4-pyrimidinyl]-4-(tert-butyl)benzenesulfonamide (EP 0658548B1) dissolved in 0.5 mm of dimethylsulfoxide was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 3 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)CCCCCCl
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CCCCCCl)OCc1ccccc1
Yield: 85.2 %

Procedure:
46.5 g (0.3 mole) of 6-chlorohexanoic acid and 35.6 g of benzyl alcohol in 500 ml of toluene are heated in the presence of 1 g of p-toluenesulphonic acid, using a water separator. When the reaction has ended, the mixture is washed with 5% strength sodium bicarbonate solution and water, dried with sodium sulphate and concentrated and the residue is distilled, 61.5 g (85% of theory) of benzyl 6-chlorohexanoate of boiling point 163° to 165°/4 mm being obtained.
Reaction SMILES: [Li][C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2S(=O)(=O)C3C(=CC=CC=3)[O:23][C:22]=2[CH:21]=CC=1.C(=O)C>>[OH:23][CH:22]([C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: O=S1(=O)c2ccccc2Oc2ccccc21
Reactant: [Li]c1cccc2c1S(=O)(=O)c1ccccc1O2
Agent: CC=O
Product: CC(O)c1cccc2c1S(=O)(=O)c1ccccc1O2
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
To a batch of 1-lithiophenoxathiin 10,10-dioxide, prepared according to the procedure of Example 1B from 44 g of phenoxathiin 10,10-dioxide chilled to ≤-50° C. in a dry ice/acetone bath, was slowly added chilled acetaldehyde (20.37 g). The reaction mixture was maintained at -50° C. during the addition which took 45 min. It was then allowed to warm to room temperature, and the solvent was removed under reduced pressure. The yellow-orange residue was stirred overnight with 0.5 N hydrochloric acid (259 mL), filtered and washed with water (500 mL). It was then washed throughly with ethanol (1.5 L), filtered and dried to give 1-(1-hydroxyethyl) phenoxathiin 10,10-dioxide (41 g) which was sufficiently pure for the next step (conversion to 1-ethylphenoxathiin 10,10-dioxide).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5]O>C(O)C.[Pd]>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH2:5]
Reactant: COc1cccc(C=NO)c1F
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CN)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the oxime (14) (1.50 g, 8.86 mmol) in ethanol (70 mL) under nitrogen was added 10% palladium on carbon (100 mg). The reaction mixture was placed under an atmosphere of hydrogen and stirred at RT for 2 hr. The reaction mixture was filtered through Celite™, and was then evaporated in vacuo to remove the ethanol. The resultant crude residue was partitioned between ethyl acetate (50 mL) and aq hydrochloric acid (2 M, 50 mL). The aq layer was separated and was neutralised with saturated sodium hydrogen carbonate solution and then re-extracted with ethyl acetate (70 mL) followed by a mixture of 2-propanol and chloroform (1:1, 2×70 mL). The propanol/chloroform extracts were dried, filtered and evaporated in vacuo separately to afford the title compound (15) in two batches (batch 1: 346 mg, 25%; batch 2: 370 mg, 27%) as white solids: m/z 156 (M+H)+ (ES+) (method C).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[N:4]1([C:8]2[C:13]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:22])[C:20]=3[Br:21])=O)=[C:12](Cl)[N:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5]1>N1C=CC=CC=1>[N:4]1([C:8]2[N:9]=[CH:10][N:11]=[C:12]3[N:2]([CH3:1])[N:3]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:22])[C:20]=4[Br:21])[C:13]=23)[CH2:7][CH2:6][CH2:5]1
Reactant: CNN
Reactant: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1Br
Solvent: c1ccncc1
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1Br
Temperature: 85 °C

Procedure:
A mixture of methylhydrazine (98%, 1.57 mL, 29.2 mmol) and [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl](5-bromo-1-methyl-1H-pyrazol-4-yl)methanone (C27) (1.04 g, 2.92 mmol) in pyridine (15 mL) was heated to 85° C. for 16 hours. Volatiles were removed in vacuo and the residue was purified using silica gel chromatography (Gradient: 0.5% to 5% methanol in ethyl acetate) to provide the product as a solid. Yield: 960 mg, 2.76 mmol, 94%. LCMS m/z 348.3, 350.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.25-2.34 (m, 2H), 3.84-4.04 (br m, 4H), 3.97 (s, 3H), 4.05 (s, 3H), 7.67 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:36]([O:40][CH2:41][CH3:42])(=[O:39])[CH:37]=[CH2:38]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([O:40][C:36](=[O:39])[CH:37]=[CH:38][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH3:42]
Reactant: C=CC(=O)OCC
Reactant: OCc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(CO)cc1

Procedure:
4-Bromobenzyl alcohol (10.5 g, 56.1 mmol), triphenylphosphine (0.5 g, 1.9 mmol) and palladium acetate (0.5 g, 2.2 mmol) were stirred at reflux in ethyl acrylate (20 mL) and triethylamine (100 mL) for 72 hours, then allowed to cool. The reaction mixture was filtered through celite (Diatomaceous Earth), then concentrated. The crude solid was purified by chromatography on silica gel (20% v/v ethyl acetate in petroleum ether) to afford the title compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@@H:9]1[C:18]([OH:20])=[O:19])=O)(C)(C)C.[ClH:21].CCOC(C)=O>>[ClH:21].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C[C@@H]1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN[C@@H](C(=O)O)C1

Procedure:
A solution of (2R)-1-tert-butoxycarbonyl-4-methanesulfonylpiperazine-2-carboxylic acid (2.90 g) in 4N HCl-AcOEt solution (40 ml) was stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and the residue was solidified with Et2O to give 2.15 g of (2R)-4-methanesulfonylpiperazine-2-carboxylic acid hydrochloride as a powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12].[H][H].Cl>[Ni].C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1c(Cl)ccc(O)c1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)ccc(O)c1Cl
Yield: 70.4 %

Procedure:
85 g. of 2,4-dichloro-3-nitrophenol was reduced in 900 ml. of ethanol with 9 g. of Raney nickel as a catalyst at 40° C. and 20 excess atmosphere hydrogen pressure. After the reduction, the solution was liberated of the catalyst, acidified with hydrochloric acid, and prepared in the usual manner. 62 g. of 2,4-dichloro-3-aminophenol hydrochloride (equivalent to 70.4% of theory) was obtained in the form of white crystals with a decomposition point of 177°-183° C. The mass spectrum showed 178 mols (calc. 178). Analysis yielded the following values:
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[C:8]([O:12][C:13]([NH:15][CH2:16][C@@:17]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][C@H:22]2[C@@H:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH2:21]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].CI>O>[C:8]([O:12][C:13]([N:15]([CH2:16][C@@:17]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][C@H:22]2[C@@H:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH2:21]2)[CH3:4])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Sodium hydride (63%, 2.48 g, 65.0 mmol) was added in small portions to a tetrahydrofuran solution (25 mL) of [(1S,5R,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (2.01 g, 6.50 mmol) and methyl iodide (4.05 mL, 65.0 mmol) with stirring at room temperature. The mixture was stirred at this temperature for 6 hours, and water (50 mL) was then added thereto while the reaction solution was cooled on ice, followed by washing with diethyl ether. The aqueous layer was made acidic using 1 M citric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (2.00 g, 95%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:41]([N:48]1[CH2:52][CH2:51][N:50]([C@@H:53]([C:57]([CH3:60])([CH3:59])[CH3:58])[C:54](O)=[O:55])[C:49]1=[O:61])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:41]([N:48]1[CH2:52][CH2:51][N:50]([C@@H:53]([C:57]([CH3:59])([CH3:58])[CH3:60])[C:54]([NH:1][C@@H:2]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:55])[C:49]1=[O:61])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
A solution containing the product from Example 92J (0.050 g, 0.092 mmol) in THF (1 mL) was treated with the product from Example 70A (0.028 g, 0.097 mmol), DEPBT (0.041 g, 0.137 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.036 g, 48% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(s, 9H), 0.89(s, 9H), 1.60-1.49(m, 2H), 2.32(s, 3H), 2.60-2.53(m, 1H), 2.68-2.65(d, J=6.99 Hz, 2H), 2.88-2.75(m, 2H), 2.96-2.90(q, J=8.70 Hz, 1H), 3.24-3.15(m, 1H), 3.51(s, 3H), 3.71-3.61(m, 1H), 3.87-3.83(d, J=9.56 Hz, 1H), 4.09(s, 1H), 4.22-4.11 (m, 2H), 4.31(s, 2H), 4.56-4.53(d, J=7.72 Hz, 1H), 6.67-6.63(d, J=9.56 Hz, 1H), 7.08-7.02(m, 5H), 7.21-7.19(d, J=8.46 Hz, 2H), 7.31-7.26(m, 3H), 7.40-7.35(m, 2H), 7.50-7.46 (d, J=9.56 Hz, 1H), 7.68-7.64(dd, J=8.27, 2.02 Hz, 1H), 7.82-7.77(m, 2H), 7.88-7.85(d, J=8.09 Hz, 2H), 8.47-8.46(d, J=2.21 Hz, 1H).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)[CH3:3]>CCO.C(Cl)Cl.[Pd]>[CH:2]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc2c(c1)nc(N)c1ncccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Pd/C (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The Pd/C was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-60% EtOAc/Hexanes to give 8-isopropylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid: 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.37 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H), 7.27 (dd, 1H), 6.66 (br s, 2H), 3.10-3.00 (m, 1H), 1.33 (d, 6H). LRMS [M+11]=238.1.
Reaction SMILES: CS(C)=O.[CH:5]([C:7]1[O:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].C(O[K])(C)=O.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][NH:25][C:24]2=[O:31]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:31]=[C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:10]3[O:11][C:7]([CH:5]=[O:6])=[CH:8][CH:9]=3)[CH:22]=2)[N:27]=[CH:26][NH:25]1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd+2]
Agent: CC(=O)O[K]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A 5:2 v/v mixture of DMSO and H2O (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. 5-Formylfuran-2-ylboronic acid ((VIa); 26.8 g, 193 mmol) was added dissolved in this mixture. [HP(t-Bu)3]BF4 (840 mg, 2.94 mmol) and Pd(OAc)2 (680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 20 min AcOK (18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min at ambient temperature. 6-Iodoquinazolin-4(3H)-one ((Va); 40 g, 147 mmol) was added and heated to 80±5° C. (internal temperature) in an oil bath under nitrogen. Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80±5° C.) was added into the filtrate. This was slowly cooled to 0-15° C. (solid started to precipitate at 70° C. (internal temperature) and was then filtered. The filter cake was washed with H2O (80 mL), then with MeCN (60 mL), and dried in vacuo at 60±5° C. for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2-carbaldehyde ((IX); 34.6 g, 144 mmol) with 99.7% HPLC purity in 97.6% HPLC yield. 1H NMR (300 MHz, d6-DMSO): δ 7.47 (d, J=3.8 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, J=8.6, 2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 110.5, 122.6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178.8; ESI-MS, Pos: [M+H]+ m/z 241; IR (cm−1): 1713, 1671, 1604,1462; m.p.: 267° C. See FIG. 2 for the DSC/TGA of the compound of formula (IX); See FIG. 3 for the X-ray powder diffraction pattern of the compound of formula (IX); Residual concentration of palladium: 230 ppm.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([F:33])[F:32])[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([F:32])[F:33])[CH2:25][N:1]1[CH:2]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccc(OC(F)F)c(Cl)c1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-chloro-4-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 427.96 g/mol.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:4]=1[F:11].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([O:12][CH2:2][C:3]2[C:4]([F:11])=[CH:5][CH:6]=[C:7]([F:10])[C:8]=2[F:9])[CH:18]=1
Reactant: Cc1ccnc(O)c1
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2c(F)ccc(F)c2F)c1
Yield: 15.5 %

Procedure:
A mixture of 8.32 g (36.96 mmol) of 2-(bromomethyl)-1,3,4-trifluorobenzene and 4.84 g (44.35 mmol) of 2-hydroxy-4-methylpyridine [CAS No.: 13466-41-6] was dissolved in 227 ml of THF. The solution was admixed with 12.23 g (44.35 mmol) of silver carbonate and the mixture was heated to reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr and washed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by means of silica gel chromatography (eluent:cyclohexane/dichloromethane gradient: 10/0 to 1/1). 1.45 g of the title compound were obtained (15% of theory).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:8]([F:11])=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To 3-acetamido-6-fluorobenzotrifluoride (2.4 g, 10.85 mmol) in concentrated H2SO4 (10 mL) at 0° C. was added dropwise 70% HNO3 (1.5 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (20 g). The precipitate was collected by filtration, affording 2.6 g (90%) of crude 3-acetamido-6-fluoro-4-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to give 2.1 g of pure compound as yellow needles. 1H NMR (CDCl3): δ 2.318 (s, 3H), 8.062 (d, 1H, J=9.6 Hz), 9.196 (s, 1H), 10.152 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][C:15]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][C:8](=[O:10])[CH:7]=[CH:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH3:21])=[CH:16][C:15]=1[N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CC(N)c1ccc(F)c(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)C=Cc1ccc(F)cc1)c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 4-fluorocinnamic acid (3.16 g, 19.6 mmol), 1-(4-Fluoro-3-morpholin-4-yl-phenyl)-ethylamine (4.39 g, 19.1 mmol), EDC.HCl (7.53 g, 39.2 mmol), DMAP (2.39 g, 19.6 mmol) and Et3N (8.23 ml, 58.8 mmol) in CH2Cl2 (60 ml) was stirred at room temperature for 16 hours. Purification by flesh chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 6.9 g of the title compound. The enantiomer was separated by Chiralpak AD column (50×500 mm, 20um) eluted with 45% EtOH in hexane, RT=36.1 min.