Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:19]([NH2:21])=[O:20])=[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:6]=1.[N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:22]1([C:2]2[S:3][C:4]([C:19]([NH2:21])=[O:20])=[C:5]([O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([F:18])([F:17])[F:16])[N:6]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.050 g, 0.14 mmol) and benzimidazole (0.010 g, 0.08 mmol) in DMF (4 mL) was heated at 75° C. in the presence of K2CO3 (0.011 g, 0.08 mmol) for 12 h. After the reaction mixture had cooled to rt, it was diluted with EtOAc (10 mL), washed with H2O (4×10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.96 (d, J=7.7 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.54-7.40 (m, 3H), 6.80 (bs, 1H), 5.82 (s, 2H), 5.63 (bs, 1H). MS m/z 419 (m+1).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][C:5]=1[C:12]([OH:14])=O)([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[NH:6][C:5]=1[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:14])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)c1cc(C(C)C)c(C(=O)O)[nH]1
Product: CC(C)c1cc(C(C)C)c(C(=O)Nc2ccc(C(=O)O)cc2)[nH]1

Procedure:
In the same manner as that of Example 17, 3,5-diisopropylpyrrole-2-carboxylic acid (60 mg, 0.308 mmol) was condensed with methyl 4-aminobenzoate, the reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography [hexane-ethyl acetate (3:1)] to obtain the desired condensate (60 mg, 59%) from the high polarity portion, and the starting material substrate acid anhydride (15 mg, 26%) from the low polarity portion.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:30][CH:31]=2)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:32])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCO)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NCCO)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-N-(2-hydroxy-ethyl)-benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless foam containing 7% of the corresponding Z isomer, MS (ESI+): m/z=472.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:20](=[O:21])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([N:17]=[N+]=[N-])[C:11]=4[CH:10]=[CH:9][N:8]=3>CO>[CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:20](=[O:21])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([NH2:17])[C:11]=4[CH:10]=[CH:9][N:8]=3
Reactant: [N-]=[N+]=Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Solvent: CO
Product: Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Yield: 48.1 %

Procedure:
A solution of 4-azidosampangine (273 mg, 1.0 mmol) in MeOH (50 mL) was heated at reflux for 7 days. Following evaporation of the solvent, the residue was chromatographed as above to give 4-aminosampangine (23) (119 mg, 48%).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][C:4](=[O:19])[CH2:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.CN>>[CH3:23][N:24]1[CH:26]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:6](=[O:18])[C:5]([C:4](=[O:19])[CH2:3][CH:2]([CH3:20])[CH3:1])=[CH:25]1
Reactant: CC(C)CC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Agent: Cl
Product: CC(C)CC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 3.9 g. portion of impure 6-methyl-1-(3-trifluoromethylphenyl)-2,4-heptanedione was reacted with 50 ml. of N,N-dimethylformamide dimethyl acetal, and then with 5 g. of methylamine hydrochloride as described in the examples above. The product was purified as described in Example 13 to obtain 0.22 g. of the desired product, m.p. 110°-112°. Nmr analysis is DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, atomatic); 3.8 (s, 3H, N--CH3); 2.9-3.1 (d, 2H, COCH2); 1.8-2.4 (m, 1H, CH2CH); 0.8-1.0 (d, 6H, CH(CH3)2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=1.[CH3:19][NH:20][CH3:21].O>CS(C)=O>[CH3:19][N:20]([CH3:21])[C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[O:18])=[CH:12][CH:13]=1
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(F)cc1
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C)c1NC(=O)c1ccc(N(C)C)cc1
Temperature: 150 °C

Procedure:
Ten grams of N-(2,6-dimethylphenyl)-4-fluorobenzamide were dissolved in 50 ml of dimethylsulfoxide in a high pressure/temperature bomb. Anhydrous dimethylamine (18.5 g) was added and the reaction vessel sealed and heated at 150° C. for 18 hours. The bomb was cooled and the contents poured into water. The mixture was extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was crystallized from methanol/water affording the desired title product in yield, m.p. 215-217° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=3[C:17]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=[CH:6]2.B(Br)(Br)Br>>[CH2:18]([C:17]1[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14][C:13]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Agent: BrB(Br)Br
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Yield: 64.9 %

Procedure:
Following the procedure described in Step 3 of Example 1, the title compound was prepared from 2-(6-methoxy-naphthalen-2-yl)-3-pentyl-benzofuran (8.0 g, 23.3 mmol) and boron tribromide (70 mL of 1 M solution in methylene chloride, 70 mmol). Purification by chromatography on a Biotage apparatus using 4% ethyl acetate in hexane as the mobile phase afforded the title compound as a solid (5.0 g), mp 100-102° C. Mass spectrum (+APCl, [M+H]+) m/z 331. 1HNMR (300 MHz, DMSO-d6): δ9.94 (s, 1H), 8.17 (s, 1H), 7.9 (d, 1H, J=8.8 Hz), 7.84-7.75 (m, 2H), 7.65 (m, 1H), 7.58 (d, 1H, J=7.3 Hz), 7.34-7.23 (m, 2H), 7.16-7.12 (m, 2H), 2.69 (t, 2H, J=7.5 Hz), 1.71 (p, 2H, J=6.9 Hz), 1.42-1.25 (m, 4H), and 0.83 ppm (t, 3H, J=6.9 Hz). Elemental Analysis for C23H22O2.0.2H2O: Calculated: C, 82.70; H, 6.76; N, 0.00. Found: C, 82.82; H, 6.73; N, 0.09.
Reaction SMILES: [N:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ncccc12

Procedure:
A mixture of 17.8 g of Pyrido[2,3-d]pyrimidin4(3H)one and 200 mL of POCl3 was stirred under reflux for one hour. Excess POCl3 was removed under vacuum, and then CH2Cl2, ice, and water were added. A black solid dissolved slowly. The organic layer was then separated, washed with aqueous NaHCO3, and dried over Na2SO4. Solvent was then removed under vacuum to leave a yellow solid, which was recrystallized from toluene/hexane. M.P. 137° dec.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:26])([CH3:25])[CH2:12][O:13]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.Cl.S([O-])([O-])(=O)=O.[Mg+2]>CO.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:26])([CH3:25])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: C[C@@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
(S)-2-Chloro-4-nitro-1-[2-hydroxy-3-(4-nitrobenzoyloxy)-2-methylpropyl]imidazole prepared in Example 15 (6.8 g, 17.67 mmol) was dissolved in methanol (68 ml). Potassium carbonate (122 mg, 0.88 mmol) was added to the solution, and the resulting mixture was stirred at room temperature overnight. The mixture was cooled on ice-bath, 6N hydrochloric acid (0.3 ml) and magnesium sulfate (3 g) were added to the mixture in this order, and the mixture was stirred for 30 minutes. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (3.4 ml) and toluene (34 ml) were added to the residue, and the resulting precipitates were filtered off to afford (S)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole (4.09 g, yield 97%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:41][CH3:42])=[N:28][CH:29]=[C:30](B5OC(C)(C)C(C)(C)O5)[CH:31]=4)=[CH:24][N:23]=[C:22]([S:43][CH3:44])[N:21]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:49]1[C:50]([CH3:55])=[N:51][NH:52][C:53]=1[CH3:54].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[Na+].O.C(OCC)(=O)C>[Pd](Cl)Cl.O.C1COCC1>[F:47][C:2]([F:46])([F:1])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:41][CH3:42])=[N:28][CH:29]=[C:30]([C:49]5[C:50]([CH3:55])=[N:51][NH:52][C:53]=5[CH3:54])[CH:31]=4)=[CH:24][N:23]=[C:22]([S:43][CH3:44])[N:21]=3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1n[nH]c(C)c1Br
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(-c2c(C)n[nH]c2C)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-2-(methylthio)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (Step A, 0.76 g, 1.11 mmol), 4-bromo-3,5-dimethyl-1H-pyrazole (0.233 g, 1.33 mmol), tripotassium phosphate (1.178 g, 5.50 mmol), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (0.087 g, 0.11 mmol), THF (8.33 mL), and H2O (2.77 mL) were sealed in a microwave vessel and subject to microwave irradiation at 120° C. for 1.5 hrs. The resulting reaction mixture was worked up with brine/ethyl acetate. The combined extracts were dried over Na2SO4, filtered and evaporated to afford a brown mixture. This mixture was purified by flash chromatography (SiO2, ISCO, RediSep 24 g Cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 50% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford an off-white solid of 450 mg as the titled compound. LCMS (M+H)+: 653.35.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([S:15]C(=O)C)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.[OH-].[Na+]>CC(OC)(C)C>[SH:15][CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CC(=O)SC(C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CC(S)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.3 %

Procedure:
In a synthesis carried out according to Hoppe, et al., Angew. Chem. Int. Ed., 36(24), 2784 (1997), at room temperature, 2.1 g of lithium aluminum hydride and 100 mL of methyl tertiary butyl ether are added to a 250 mL round-bottom flask. To this suspension 18 g of thioacetic acid S-(1-phenyl-ethyl)ester in 50 mL MTBE is added. The mixture is stirred for 15 h at room temperature. 5 mL of ethyl acetate and 2.5 mL of sodium hydroxide (1 M in water) are added. The reaction mixture is filtered over a sodium sulphate plug. The filtrate is concentrated to give 13.7 g of a yellow liquid which is purified by distillation.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH2:20].C(O)(=O)C>CO>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[N:20][NH:19][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a stirred solution of 1-(diphenylmethyl)azetidin-3-one (Preparation 693, 11.4 g, 48 mmol) and tert-butyl hydrazinecarboxylate (6.3 g, 48 mmol) in methanol (110 ml) at 0° C. was added acetic acid (5.56 ml, 96 mmol) dropwise and stirred at room temperature for 18 hours. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (500 ml). The organic layer was washed with 1M aqueous sodium hydroxide solution (2×150 ml), water (3×150 ml), saturated aqueous sodium chloride solution (150 ml), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was triturated with diethyl ether to get 15.8 g (94%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[C:31]1[CH:32]=[C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)[CH:34]=[CH:35][C:30]=1[Cl:29])[CH3:43]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with 4-chloro-3-(ethoxycarbonyl)benzeneboronic acid, copper-(II)-acetate and pyridine to give the title compound as a off-white solid. MS (m/e, ISP neg. ion)=596.3 [M−H+]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]2=[N:4][CH:3]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([Cl:16])=[O:13])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ncc(Cl)nc2s1
Product: O=C(Cl)c1cc2ncc(Cl)nc2s1
Yield: 98.8 %

Procedure:
A solution of 3-chlorothieno[2,3-b]pyrazine-6-carboxylic acid 93 (0.191 mmol, 41 mg) in thionyl chloride (27.4 mmol, 2 ml, 3262 mg) was heated at 80° C. for 2 h. Reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (2×) to give 3-chlorothieno[2,3-b]pyrazine-6-carbonyl chloride 94 (44 mg, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[NH:28][C:27]1=[O:32])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (562 mg), 5-methoxy-2-oxindole (326 mg), and piperidine (2 drops) in ethanol (2 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added, the temperature was increased to 95° C. and held there for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 240 mg (65%) of 4-(2-carboxy-ethyl)-3-methyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=[O:21]>CN1C(=O)CCC1>[CH2:1]([O:8][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To benzyl alcohol (1.1 g, 10 mmol) in NMP (20 mL) was added sodium hydride (60% in mineral oil; 0.44 g, 11 mmol), and the mixture was stirred for 30 minutes at room temperature. The mixture was then added to a vial containing 2-chloro-5-fluorophenylacetic acid (1 g, 4.5 mmol), and the reaction was stirred at 120° C. for 3 hours. Acidic work-up gave the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)(=[O:9])[CH3:8].C(NCCCCCCCCCCC(Cl)=O)(=O)C.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48][CH3:49].[Cl-].[Al+3].[Cl-].[Cl-].Cl>CN(C=O)C.C(Cl)Cl.O>[F:41][C:42]1[CH:47]=[C:46]([C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7](=[O:9])[CH3:8])[CH:45]=[CH:44][C:43]=1[O:48][CH3:49]
Reactant: COc1ccccc1F
Reactant: CC(=O)NCCCCCCCCCCC(=O)O
Agent: CC(=O)NCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCCCCCCNC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
0.5 ml of oxalyl chloride is added to a solution of 1.2 g of 11-acetylamino-undecanoic acid and 5 drops of DMF in 15 ml of methylene chloride at 0° C. and the mixture is stirred at RT for 3 hrs. The solution of the 11-acetylamino-undecanoyl chloride is treated under argon with 0.6 g of 2-fluoroanisole, cooled to -15° C. and treated with 1.4 g of aluminium chloride. After 2 hrs. at -15° C. the mixture is left to warm to room temperature overnight. The solution is treated with 15 ml of 1 M hydrochloric acid at 0° C. and then with 20 ml of water. The organic phase is separated and washed with 1M hydrochloric acid, with water and with saturated sodium bicarbonate solution, dried and concentrated. 1.8 g of N-[11-(3-fluoro-4-methoxy-phenyl)-11-oxo-undecyl]acetamide are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)O)=[CH:4][CH:3]=1.Br>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(C(O)(c2ccc(F)cc2)c2cccnc2)CC1
Agent: Br
Solvent: O
Product: CN1CCC(=C(c2ccc(F)cc2)c2cccnc2)CC1
Yield: 48 %

Procedure:
A mixture of 240 parts of α-(4-fluorophenyl)-α-(1-methyl-4-piperidinyl)-3-pyridinemethanol and 900 parts of a hydrobromic acid solution 48% in water was stirred and refluxed for 1 hour. The whole was concentrated to one third of its volume. The concentrate was treated with a sodium hydroxide solution. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of petroleumether and a small amount of 2,2'-oxybispropane (10:1 by volume). The product was filtered off and dried, yielding 112.5 parts (48%) of 3-[(4-fluorophenyl)(1-methyl-4-piperidinylidene)methyl]pyridine; mp. 93.1° C. (intermediate 19).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:3]=1.[NH3:20]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:20])[CH:5]=[C:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(Cl)cc(-c2c(Cl)cccc2Cl)nc1Cl
Solvent: CO
Product: Nc1cc(-c2c(Cl)cccc2Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,4-Dichloro-6-(2,6-dichloro-phenyl)-3-nitro-pyridine (94.4 mg, 0.279 mmol, prepared as described in the previous step) was placed in a 8 mL vial equipped with a stir bar and dry MeOH (2 mL) was added via syringe. The resulting solution was gently heated with a heat gun to dissolve the solid and 7M NH3 in MeOH (2.00 mL, 14.0 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 16 h and the solvent was removed under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (TLC) on a 2000μ SiO2 plate developed with 1:4 EtOAc/heptane to yield 2-chloro-6-(2,6-dichlorophenyl)-3-nitropyridin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.33-7.45 (m, 2H), 7.27-7.33 (m, 1H), 6.68 (s, 1H), 5.86 (br. s., 2H). LCMS (ESI): Calculated for C11H6ClN3O2: 318.0 (M+H); Measured: 318.0.