Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21]CC3C=CC=CC=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2].[H][H]>[Pd].CO.CN(C=O)C.ClC(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Yield: 107.6 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6methoxyquinazoline (2.18 g, 7.25 mmol), 3-acetoxy-4-methylaniline (1.32 g, 8 mmol) and 2-propanol (50 ml) was stirred and heated to reflux for 1 hour. The mixture was cooled to ambient temperature. The precipitate was collected by filtration, washed with 2-propanol and ether to give 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline. A mixture of 4-(3-acetoxy-4-methylanilino)-7-benzyloxy-6-methoxyquinazoline (2.68 g, 5.75 mmol), 10% palladium-on-charcoal catalyst (0.27 g) in methanol (50 ml), DMF (12 ml) and trichloromethane (50 ml) was stirred at ambient temperature under 1.5 atmospheres of hydrogen for 30 minutes The catalyst was removed by filtration and the filtrate evaporated. The residual solid was triturated in ether, collected by filtration and dried under vacuum at 50° C. to give 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (2.1 g, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:17])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[S:8][C:7]([CH3:17])=[N:6][C:5]=2[C:3]([OH:4])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc(C)sc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid methyl ester (15 g) in a mixture of THF (60 mL) and MeOH (20 mL) was added a solution of sodium hydroxide (2.63 g) in water (60 mL). The reaction mixture was stirred at RT for 30 min. The reaction mixture was then concentrated in vacuo, and the residue was dissolved with water (100 mL) and concentrated again in vacuo. The residue was dissolved in water (250 mL), cooled to 0° C. with a ice-bath. Then was added a solution of conc.HCl (37%)(7.72 g) in water (7.72 g) and stirred at 0° C. for 15 min. The resulting precipitate was filtered off, washed with water and dried in high vacuum pump. to give the title compound as a white solid (13.16 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]([C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:14](=O)[CH2:15]Br)([CH3:10])([CH3:9])[CH3:8].N.O>C(C(C)=O)C.C(O)C>[C:22]([C:19]1[CH:18]=[C:13]([C:14]2[N:1]=[C:2]3[N:6]([CH:15]=2)[CH2:5][CH2:4][S:3]3)[CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:20]=1[OH:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: NC1=NCCS1
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Agent: N
Solvent: CCC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
In 300 ml of methyl ethyl ketone was dissolved 10.2 g of 2-amino-2-thiazoline and after adding 32.7 g of 3,5-di-tert-butyl-4-hydroxyphenacyl bromide was added portionwise to the solution followed by stirring for 30 minutes at room temperature, the resultant mixture was refluxed for one hour. Then, the solvent was distilled off under reduced pressure, the crystals thus formed were dissolved in 200 ml of ethanol, and the solution was refluxed for 4 hours. The reaction mixture was basified with the addition of aqueous ammonia and then 200 ml of water was added to the reaction mixture to precipitate crude crystals, which were recovered by filtration and recrystallized from ethanol to provide 23.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH2:36][CH3:37])[CH2:34][OH:35].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[OH:35][CH2:34][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH2:36][CH3:37]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC[C@H](CO)NC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O[C@@H](C)COC)c2)[nH]1
Reaction time: 6 h
Yield: 84.8 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k), (R)-(−)-2-amino-1-butanol (0.38 mL, 4.03 mmol), HOBT.H2O (0.44 g, 3.23 mmol) and N-methylmorpholine (0.59 mL, 5.38 mmol) were dissolved in methylene chloride (30 mL), and WSCI.HCl (0.62 g, 3.23 mmol) was added at room temperature, followed by stirring for 6 hours under nitrogen atmosphere. The reaction solution was diluted with methylene chloride (50 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (1.18 g, 85%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][N:28]2[C:32]([CH2:33][CH2:34][NH2:35])=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[C:21]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][N:28]2[C:32]([CH2:33][CH2:34][NH:35][C:18]([C@@H:17]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][N:8]3[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:20])=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NCCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydro-isoquinoline-3(S)-carboxylic acid (0.15 g, 0.54 mmol) and 3-(4-cyanobenzyl) histamine (0.122 g, 0.54 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole (0.083 g, 0.54 mmol), EDC (0.104 g, 0.54 mmol), and N-methylmorpholine (0.24 mL, 2.16 mmol). After stirring for 18 hr. the mixture was evaporated in vacuo and the residue was partitioned with EtOAc (50 mL) and saturated NaHCO3 (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration was done which gave the title compound.
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:10]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
Methylmagnesium chloride (9.53 mL, 3.0M tetrahydrofuran solution) was added to tetrahydrofuran (45.5 mL). Benzyl 4-oxopiperidine-1-carboxylate (5.00 g) was dissolved in tetrahydrofuran (8.8 mL), and added dropwise to a solution of ice-cooled methylmagnesium chloride in tetrahydrofuran, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was ice-cooled, aqueous ammonium chloride solution (ammonium chloride 1.41 g, water 15 mL) was added dropwise, and the mixture was partitioned and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over magnesium sulfate, and purified by NH-silica gel column chromatography [developing solvent; hexane:ethyl acetate=80:20 (volume ratio)→60:40 (volume ratio)]. The obtained solid was washed with isopropyl ether, and dried under reduced pressure to give the title compound (4.20 g, yield 79%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]([NH2:11])=[S:10])[CH2:3][CH2:2]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[CH2:23]=O>CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:9]([NH:11][CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[S:10])[CH2:3][CH2:2]1
Reactant: C=O
Reactant: C1CCNC1
Reactant: NC(=S)C(CN1CCOCC1)c1ccccn1
Solvent: CO
Product: S=C(NCN1CCCC1)C(CN1CCOCC1)c1ccccn1

Procedure:
The above prepared 3-morpholino-2-(2-pyridyl)thiopropanamide is reacted with pyrrolidine and formaldehyde in methanol by the procedure of Example 2 to give 3-morpholino-N-pyrrolidinomethyl-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7](=[O:11])OCC)=[O:5])#[N:2].[CH3:12][O:13][C:14]1[CH:25]=[C:24]2[C:17]([NH:18][CH:19]=[C:20]2[CH2:21][CH2:22]N)=[CH:16][CH:15]=1>C(O)(=O)C.[Pd]>[CH3:12][O:13][C:14]1[CH:25]=[C:24]2[C:17](=[CH:16][CH:15]=1)[NH:18][C:19]1[CH:1]3[CH2:3][C:4](=[O:5])[NH:6][C:7](=[O:11])[N:2]3[CH2:22][CH2:21][C:20]2=1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCOC(=O)NC(=O)CC#N
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCN1C(=O)NC(=O)CC31
Reaction time: 72 h
Yield: 40 %

Procedure:
Ethyl cyanoacetylcarbamate (156 mg) and palladium-on-charcoal (0.6 g) are successively added to 5-methoxytryptamine (119 mg) dissolved in acetic acid. The mixture is stirred under a hydrogen atmosphere for 72 h. The medium is then filtered and the palladium is washed with a chloroform/methanol mixture. After evaporation of the solvent, the crude product obtained, dissolved in toluene, is refluxed overnight. The 9-methoxy-1,2,3,4,6,7,12,12b-octahydropyrimido[6,1-a]-β-carboline-2,4-dione precipitates and is recovered by simple filtration (40% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:11][N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH2:14][C:15]=3[C:6]2=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:4]=1[Cl:33].[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:1][CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:11][N:12]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:14][C:15]=3[C:6]2=[C:5]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:4]=1[Cl:33])(=[O:36])[CH3:35]
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2c(Cl)c(CNC(C)=O)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the compound (0.3 g) obtained in Example 18B, acetic anhydride (0.142 g) and pyridine (2.5 ml) was stirred at room temperature for 1 hour and concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to yield 2-acetylaminomethyl-7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine as an oil, which was then treated with ethanolic hydrochloride to yield the hydrochloride which was recrystallized from dichloromethane-ethyl ether to yield light-yellow powder having a melting point of 172 to 174° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(N(C)C)=O.C([SiH](CC)CC)C>O1CCCC1.C([Pd]Cl)C=C.O>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C#Cc2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: C=CC[Pd]Cl
Agent: CC[SiH](CC)CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a flask was successively added N-(4-((3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)ethynyl)phenyl)methanesulfonamide (6) (20 g; 42.60 mmol); allylpalladium(II) chloride (0.39 g; 1.06 mmol); triphenylphosphine (1.12 g; 4.26 mmol) and a solution of dimethylacetamide (80 ml)/water (2.3 ml) previously purge with nitrogen. The solution was heated at 70° C. for 30 minutes. To the reaction mixture was then added over 3 hours triethylsilane (7.42 g; 63.90 mmol). The mixture was stirred for 12 hours at 70° C. The reaction was cooled at 23° C. then diluted with tetrahydrofuran (180 ml) and successively washed with a solution of 1% Cysteine/2.5% NaHCO3/7% NaCl and a solution of 2.5% NaHCO3/7% NaCl. The organic layer was treated with activated carbon and the filtrate was concentrated down and solvent switched to methanol. The slurry was mixed at 62° C. for 60 minutes, cooled down to 25° C., mixed for 2 hours, filtered, and washed with methanol to give the titled compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (s, 9 H) 2.99 (s, 3 H) 3.76 (s, 3 H) 5.62 (d, J=7.82 Hz, 1 H) 7.12-7.29 (m, 5 H) 7.51-7.65 (m, 3 H) 7.72 (d, J=7.82 Hz, 1 H) 9.83 (s, 1 H) 11.39 (s, 1 H) MS (APCI) m/z 470.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CO[CH:13](OC)[CH2:14][C:15](=O)[CH3:16]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:14][C:15]([CH3:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: COC(CC(C)=O)OC
Solvent: CCO
Solvent: O
Product: Cc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Yield: 66.3 %

Procedure:
A solution of of 3,4-dichlorophenylhydrazine (4.27 g, 20.0 mmol) in EtOH (50 ml) and H2O (50 ml) was treated with 3-oxobutyraldehyde dimethyl acetal (2.64 g, 20.0 mmol) and refluxed for 1 h. The alcohol was removed in vacuo and the aqueous residue was extracted with AcOEt (2×150 ml). The organic phase was dried (Na2SO4), filtered and evaporated. The remaining oil was chromatographed [silica, elution with gradient hexane to 10% (hexane/AcOEt=1:1)] to obtain 3.01 g (66%) of 1-(3,4-dichloro-phenyl)-3-methyl-1H-pyrazole [Mp. 57-58° C. (AcOEt/hexane), MS: m/e=226 (M+)]as off-white crystals and 1.32 g (29%) of 1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole [Mp. 46-47° C. (hexane), MS: m/e=226 (M+)]as white crystals.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.Cl.[NH2:21][C@H:22]([CH3:26])[C@H:23]([OH:25])[CH3:24].[Na+].[Cl-]>C(#N)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:21][C@H:22]([CH3:26])[C@H:23]([OH:25])[CH3:24])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1
Reactant: C[C@@H](N)[C@@H](C)O
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@@H](C)Nc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
4.8 ml (34.8 mmol) of triethylamine are added dropwise to 3.78 g (17.4 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 2.19 g (17.4 mmol) of (2R,3R)-3-amino-butan-2-ol hydrochloride in 70 ml of acetonitrile at 0° C. The mixture is slowly warmed to room temperature and then stirred for 48 hours. The mixture is added to half-concentrated NaCl solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The resulting residue is purified by HPLC. 1.45 g (5.4 mmol; 31% yield) of the product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Yield: 57 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (115 mg, 0.25 mmol) and N-bromosuccinimide (50 mg, 0.28 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (−) m/z 531.17, 533.12 (M−1, 79/81Br).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[NH3:15]>[N+](C)([O-])=O>[NH2:15][C:9]1[C:10]([F:11])=[C:2]([F:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([F:14])[C:8]=1[F:13]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Reactant: N
Solvent: C[N+](=O)[O-]
Product: Nc1c(F)c(F)c(C(=O)O)c(F)c1F

Procedure:
A mixture of 10.0 g of 2,3,4,5,6-pentafluorobenzoic acid and 400 ml of nitromethane is saturated with anhydrous ammonia at room temperature and then placed in a bomb and heated at 100° for 20 hrs. The resulting solution is evaporated and the residue crystallized from chloroform-hexane to yield 4-amino-2,3,5,6-tetrafluorobenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:26]([O-:28])=[O:27])=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13](O)[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:26]([O-:28])=[O:27])=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(O)c3ccc(OC)c([N+](=O)[O-])c3C3CCCCC32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=Cc3ccc(OC)c([N+](=O)[O-])c3C3CCCCC23)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-5-nitro-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ol (378.6 mg, 0.987 mmol), p-toluene sulfonic acid (38.0 mg, 0.197 mmol), toluene (8 mL), stir, and reflux under nitrogen atmosphere. After 1 hour, cool reaction to ambient temperature, add ethyl acetate, wash sat sodium bicarbonate solution (aq), and then with brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using 0% to 30% ethyl acetate/hexanes to yield the titled compound (234.5 mg, 68%) as a clear oil. TLC Rf=0.40 in 2:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.25 (d, 2H, J=8.4 Hz), 6.91 (d, 2H, J=8.4 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.58 (d, 1H, J=8.4 Hz), 6.37 (d, 1H, J=2.6 Hz), 3.88 (m, 614), 3.18 (s, 1H), 2.90 (m, 1H), 2.19 (d, 1H, J=14.1 Hz), 1.60 (m, 4H), 1.33 (m, 2H), 0.99 (m, 1H).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.Cl.O.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[C:12]([S:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To the compound (6) was added concentrated aqueous hydrochloric acid (50 ml). The mixture was heated at 90° C. for 2 hours and then cooled down. To the mixture were added water (50 ml) and toluene (20 ml). The aqueous layer was separated and neutralized by 30% aqueous sodium hydroxide. The compound (12) was extracted with ethyl acetate (50 ml), and the ethyl acetate layer was washed with water (30 ml). Each aqueous layer was extracted with ethyl acetate (20 ml). The ethyl acetate layer was collected and concentrated under reduced pressure to yield oily residue. To the oily residue was slowly added diisopropyl ether (50 ml) for crystallization. The obtained slurry was stirred at room temperature for 30 minutes, filtered, washed with diisopropyl ether (30 ml) and dried to yield the compound (12) (10.4 g) as a white crystal. Yield from the compound (22):82%
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (290 mg, 56%).