Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.C(Cl)(Cl)Cl.CO>COCCOCCOC>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)C1CCCCC1
Solvent: COCCOCCOC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(C(=O)C4CCCCC4)cc3)c2cc1OC
Temperature: 160 °C
Yield: 33.1 %

Procedure:
Under argon, 4-cyclohexylcarbonyl-1-hydroxybenzene (273 mg) obtained in Example 142 and 4-chloro-6,7-dimethoxyquinoline (100 mg) were dissolved in diethylene glycol dimethyl ether (0.2 ml), and the solution was refluxed at 160° C. for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was washed with brine and then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/acetone and then with chloroform/methanol to obtain 58 mg of the title compound (yield: 33%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(NN=Cc2cccnc2)cc1

Procedure:
2.2 g of 3-pyridinecarbaldehyde was dissolved in 100 ml of ethanol. The solution was added to a filtered solution of 3.6 g of p-chlorophenylhydrazine hydrochloride and 9.8 g of sodium acetate in 60 ml of 50% by volume aqueous ethanol. The resulting precipitated solid was collected and recrystallized from ethanol to give 1, as a pale yellow prisms, mp 186° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#N)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12].C[OH:29].O>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:29])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: N#Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 M solution (1.2 ml, 1.22 mmol) of diisobutylaluminum hydride in toluene was slowly added to a solution (10 ml) of 4-(4-nitrophenyl)benzonitrile (224 mg, 1 mmol) in toluene at room temperature, and they were stirred for 1 hour. After cooling to 0° C., methanol (0.4 ml) and water (0.4 ml) were slowly added to the obtained mixture, and they were stirred. The reaction mixture was dried over sodium sulfate. After the purification by the silica gel column chromatography (ethyl acetate/hexane), 4-(4-nitrophenyl)benzaldehyde was obtained in the form of a yellow solid (yield: 127 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 62A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.78 (s, 1H) 8.07 (d, J=8.48 Hz, 1H) 7.98 (d, J=1.70 Hz, 1H) 7.60 (dd, J=8.48, 2.03 Hz, 1H) 4.08 (s, 3H) 3.93-4.07 (m, 1H) 3.26-3.45 (m, 1H) 2.50-2.80 (m, 6H) 1.78-1.96 (m, 4H) 1.59 (m, 2H). MS: (M+H)+=367.
Reaction SMILES: I[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.CN(C)[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[Cs+].[Cs+].[Si](C=[N+]=[N-])(C)(C)C>CN(C=O)C>[CH3:8][C:5]1[N:4]=[C:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1nc(C)ccc1I
Reactant: c1cn[nH]c1
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)ccc1-n1cccn1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
DMF (1.5 ml) was added to a mixture of methyl 3-iodo-6-methyl-2-pyridinecarboxylate D36 (200 mg), 1H-pyrazole (98 mg, 1.444 mmol), (1R,2R)—N,N-dimethyl-1,2-cyclohexanediamine (20.54 mg, 0.144 mmol), bis(copper(I) trifluoromethanesulfonate), benzene complex (18.17 mg, 0.036 mmol) and cesium carbonate (470 mg, 1.444 mmol) in a screw-topped vial. The mixture was degassed via 3 vacuum/nitrogen cycles and heated with shaking to 120° C. for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in water/MeOH (1:1, 3 ml) and acidified to pH=2 by addition of 4 M HCl solution. The resulting mixture was evaporated to dryness under reduced pressure then the residue was triturated with DCM/MeOH (3:1, 20 ml). The mixture was filtered washing with more DCM/MeOH (3:1, 5 ml). The filtrate was treated with TMS-diazomethane solution (2 M in hexanes, 2 ml, 4 mmol) to re-esterify the acid. The reaction mixture was evaporated under reduced pressure and the residue was purified twice by flash chromatography on silica gel (Biotage Snap 10 g column, EtOAc/Cy from 20/80 to 50/50 and then Biotage KP-NH Snap 11 g column, EtOAc/DCM isocratic 1/99) to give the title compound D37 (107 mg) as a colourless gum.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=2)[CH:3]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][S:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([S:14][C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][C:19]([S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(Cl)cc2)cc1
Reactant: Sc1ccccc1
Product: CSc1ccc(-c2nnc(Sc3ccccc3)cc2-c2ccc(Sc3ccccc3)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (150 mg, 0.303 mmol) and thiophenol (119 mg) were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (85.0 mg, 39.8%). Melting point: 53.3-56.2° C.(diethyl ether-hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N(C)S(C)(=O)=O)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(N(C)S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-(3-bromo-4-methylphenyl)-N-methylmethanesulfonamide (Intermediate 197), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])[N:10]([CH3:12])[CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[C:1]([NH:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[N:10]([CH3:12])[CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1cc(/C=C/C(=O)OC)n(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(=O)Nc1cc(/C=C/C(=O)O)n(C)c1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
A solution of 4 (0.167 g, 0.667 mmol) and 0.2 M aqueous NaOH (5.7 mL, 1.13 mmol) in MeOH (10 mL) was heated under reflux for 50 min. The mixture was cooled to 0° C., 2 M aqueous HCl (0.67 mL, 1.33 mmol) was added, and the mixture was poured onto ice (50 g). The precipitate that formed was collected by filtration and washed with water to give (E)-4-butyramido-1-methyl-2-pyrroleacrylic acid (5) as yellow needles (0.133 g, 85%) mp 74-76° C. (dec.) and 165-166° C. (with evolution of gas). 1H NMR [(CD3)2SO] δ12.02 (br s, 1 H, CO2H), 9.76 (br s, 1 H, CONH), 7.44 (d, J=15.6 Hz, 1 H, H-β), 7.27 (d, J=1.6 Hz, 1 H, H-5), 6.53 (d, J=1.6 Hz, 1 H, H-3), 6.02 (d, J=15.6 Hz, 1 H, H-α), 3.66 (s, 3 H, NCH3), 2.19 (t, J=7.3 Hz, 2 H, CH2CH2CH3), 1.57 (sx, J=7.3 Hz, 2 H, CH2CH2CH3), 0.88 (t, J=7.3 Hz, 3 H, CH2CH2CH3). 13C NMR δ169.2, 168.0 (NHCO, CO2), 131.9, 117.8, 113.6, 101.9 (C-3, 5, α, β), 125.8, 124.2 (C-2, 4), 37.5 (CH2CH2CH3), 33.6 (NCH3), 18.7 (CH2CH2CH3), 13.6 (CH2CH2CH3) Anal. Calculated for C12H16N2O4: C, 61.0; H, 6.8; N, 11.9. Found: C, C, 60.8; H, 8.4; N, 11.7%.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1(=[O:20])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:9](=[O:15])[C:8]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:7]12.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:17]1[CH:16]=[C:8]2[C:9](=[O:15])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6](=[O:20])[C:7]2=[CH:19][CH:18]=1)([O-:23])=[O:22]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 25 °C

Procedure:
To a mixture of concentrated sulfuric acid (350 ml) and fuming nitric acid (d=1.52)(60 ml) was added 2-phthalimidoacetic acid (70 g) with stirring and under ice-cooling. The mixture was stirred for 1 hour under ice-cooling and for 2 hours at room temperature, and poured into ice-water (2 l). The resultant precipitate was collected by filtration and recrystallized from a mixture of water (2 l) and ethanol (1 l) to give the title compound (60 g) as light yellow sharp-pointed needles.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=2)[CH2:20][CH2:19]1>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[N:25][C:24]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[N:29][CH:28]=1
Reactant: CN1CCN(c2ncc(N)cn2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cn2)CC1
Yield: 68.6 %

Procedure:
A N,N-dimethylformamide solution (1.6 mL) of 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (254 mg, 0.77 mmol), and 2-(4-methyl-piperazin-1-yl)-pyrimidin-5-ylamine (157 mg, 0.813 mmol) is heated at 90° C. for 40 min. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 259 mg (65%) of the title compound as a yellow solid. MS (ESI) m/z 491 (M+H)+1
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])[CH:5]=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC>[N:7]1[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])=[CH:5][CH:4]=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1cc2c(C)nc(O)c(Cc3cccc(Br)n3)c2cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1cc2c(C)nc(O)c(Cc3cccc(-c4ccncc4)n3)c2cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 4-((6-bromopyridin-2-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 34150 (53 mg, 136 μmol) in EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 4-pyridinylboronic acid (17 mg, 138 μmol), Pd(PPh3)2Cl2 (10 mg, 14 μmol), a 2 N aq. Na2CO3 solution (0.30 mL, 0.60 mmol), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and the solution was filtered through a celite plug, then washed with brine (10 mL). The organic layer was isolated and the celite plug was then further washed with CH2Cl2 (50 mL) and the organic layer was washed with brine (20 mL). The organic layers were then combined, dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 16 mg of 4-(2,4′-bipyridin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-(2,4′-bipyridin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol trihydrochloride trihydrochloride 14 as a pale brown solid (20 mg, 30% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9])[CH3:2].CC(C)=O.C(O)(C)C.CCOCC>CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[CH3:2]
Reactant: CCC1CCCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCC1CCCCC1=O
Yield: 91.3 %

Procedure:
2-Ethylcyclohexanol (1.6 moles, 204 g, 226 mL) was stirred in 3.21 of acetone at 0° C. and treated with 8N Jones reagent (prepared from 106.8 g of CrO3 suspended in 92 mL of concentrated sulfuric acid and diluted to 400 mL with water) until the orange color persisted (~430 mL). Isopropanol was then added to turn the solution green again after which it was poured into 2 l of ether. The product was washed with 6×500 ml of brine, dired over MgSO4 and stripped of solvent. Short path distillation (b.p. 80°-85° C. at 25 mm) afforded 184 g (1.46 moles, 91%) of 2-ethylcyclohexanone as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](I)[CH3:23]>CN(C=O)C.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:22][CH3:23])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 5 h

Procedure:
To a suspension of 10 g (47.57 mmol) 5-hydroxy-isophthalic acid dimethyl ester and 9.86 g (71.36 mmol) K2CO3 in 50 ml DMF is added dropwise 7.67 ml (95.1 mmol) ethyl iodide. After the addition the mixture is stirred for 5 h, diluted with water and extracted with TBME. The organic phase is washed with water, dried with sodium sulfate and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]\[C:16]([OH:18])=[O:17])=[C:6]([CH3:21])[C:5]([CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1>CC(C)=O>[CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](/[CH3:20])=[CH:11]/[CH:12]=[CH:13]/[C:14](/[CH3:19])=[CH:15]/[C:16]([OH:18])=[O:17])=[C:6]([CH3:21])[C:5]([CH3:22])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)c(C)c1C
Solvent: CC(C)=O
Product: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C
Reaction time: 1 h
Yield: 80 %

Procedure:
Crude acetretin (10 g) was added to acetone (300 ml) and stirred at 25–30° C. for 1 hour under nitrogen atmosphere. The suspension was then filtered, washed with acetone (100 ml) and dried under vacuum at 25–30° C. to obtain pure acitretin (8 g, Assay 98.3% by HPLC).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:39](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:40]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
U.S. Pat. No. 7,202,368 describes an alternative process for the synthesis of dabigatran etexilate (see Scheme 2). Example 3 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (compound VII) in the presence of a coupling agent such as N,N′-carbonyldiimidazole (CDI), propanephosphonic anhydride (PPA), or pivaloyl chloride, to give ethyl 3-{[(2-{[(4-{1,2,4-oxadiazol-5-on-3-yl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound VIII), which is subsequently hydrogenated (Example 4) in the presence of a palladium catalyst to give ethyl 3-{[(2-{[(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Then, Example 5 describes the acylation of compound V with n-hexyl chloroformate (compound VI) to give dabigatran etexilate. Finally, Example 6 describes the conversion of dabigatran etexilate into its mesylate salt. Although the patent describes the HPLC purities of intermediate compounds II, VII, VIII and V, no information is given neither about the purity of the isolated dabigatran etexilate nor about its mesylate salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:14][N:15]=[N+]=[N-])[CH2:9][C@@H:10]([CH3:13])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH3:19]O>[Pd]>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:14][NH2:15])[CH2:9][C@@H:10]([CH3:13])[CH2:11][CH2:12][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC[C@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCC[C@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Reaction time: 96 h

Procedure:
A mixture of 125 (2.8 g, 10.4 mmol) and 10% Pd/C (11.0 g) in methanol (50.0 mL) was hydrogenated at 41 PSI for 96 hours. The solution was filtered to give 1.7 g of crude 126 which was used in the next step without further purification. MS, m/z (relative intensity): 244 [M+1H, 100%], 285 [M+1H+CH3CN, 25%].
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:16]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1)(=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To 300 mL of CH2Cl2 was added 3-nitrophenol (structure 64 of Scheme XVII, where R1 =H, Y=O) (15 g, 0.11 mol), pyridine (20 mL) and DMAP (10 mg). To this cooled solution (0° C.) was slowly added trimethylacetyl chloride (18 mL, 146 mmol, 1.4 equivuiv). The solution was allowed to warm to rt and stirred for 3 h. To the amber colored solution was added sat'd NH4Cl (300 mL). The organic layer was washed with 1 N HCl (2×150 mL), 10% CuSO4. 5 H2O (2×100 mL), and brine (2×100 mL). The extract was dried (Na2SO4) and concentrated in vacuo to give 22.5 g (94%) of O-pivaloyl-3-nitrophenol as a white solid. Data for O-pivaloyl-3-nitrophenol: Rf 0.55 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 8.11 (dd, J=4.2, 1.3, 1 H), 7.96 (t, J=2.2, 1 H), 7.56 (dd, J=8.4, 8.2, 1 H), 7.42 (dd, J=6.5, 1.3, 1 H), 1.35 (s, 9 H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[CH2:16][N:17]([CH3:19])[CH3:18])#N.C[OH:24].[OH-].[Na+]>C1(C)C=CC=CC=1.CO.O>[CH3:18][N:17]([CH2:16][C:15]1[CH:14]=[C:13]([CH:22]=[CH:21][CH:20]=1)[CH:11]=[O:24])[CH3:19]
Reactant: CO
Reactant: CN(C)Cc1cccc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)Cc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diisobutylaluminium hydride (1.0M solution in toluene, 20 ml, 20 mmol) was added dropwise to a solution of 3-cyano-(N,N-dimethyl)benzylamine [Example K(a)] (3.20 g, 20 mmol) in toluene (50 ml). The mixture was stirred at room temperature for 2 h., methanol (30 ml) was cautiously added, followed by methanol/water (1:1, 40 ml) and 10% aqueous sodium hydroxide (100 ml). The mixture was extracted twice with diethyl ether, washed with saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to give a yellow oil (3.0 g). M+ 163; 360 MHz 1H n.m.r (CDCl3) 10.02 (1H, s), 7.83 (1H, s), 7.79 (1H, d, J 7.6 Hz), 7.60 (1H, d, J 7.5 Hz), 7.49 (1H, t, J 7.5 Hz), 3.50 (2H, ), 2.26 (6H, s).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[C:26]=[S:27]>C(Cl)(Cl)Cl>[F:35][C:34]([F:36])([F:37])[C:30]1[CH:29]=[C:28]([NH:25][C:26]([N:3]2[CH2:4][CH2:5][S:1][C:2]2=[N:6][CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[CH2:8][C:9]2[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[S:27])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccc(Cl)c2Cl)c1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(CC(N=C2SCCN2C(=S)Nc2cccc(C(F)(F)F)c2)c2cccc(Cl)c2Cl)c1
Yield: 53.7 %

Procedure:
A solution of 1-(4,5-dihydrothiazol-2-yl)amino-1-(2,3-dichlorophenyl)-2-(3,5-dimethylphenyl)-ethane (0.25 g) in chloroform (10 ml) was treated with 1-isothiocyanato-3-trifluoromethylbenzene (0.13 g) at room temperature overnight. The solvent was evaporated in vacuo and the remainder was purified by column chromatography to yield 0.20 g of the title compound.