Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:6][C:7](=[O:9])[CH:8]=1)=[O:5])[CH3:2].[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH:24]12[CH2:31][CH2:30][CH:27]([CH:28]=[CH:29]1)[CH2:26][CH:25]2[C:32]([O:34][CH2:35][CH2:36]O)=[O:33].N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1>[CH2:1]([C:3]1[C:4]([NH:6][C:7](=[O:9])[CH:8]=1)=[O:5])[CH3:2].[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH:24]12[CH2:31][CH2:30][CH:27]([CH:28]=[CH:29]1)[CH2:26][CH:25]2[C:32]([O:34][CH2:35][CH2:36][CH2:4][OH:5])=[O:33]
Reactant: O=C(OCCO)C1CC2C=CC1CC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)OC(=O)C1CC2C=CC1C2
Agent: CCC1=CC(=O)NC1=O
Solvent: C1CCOC1
Product: O=C(OCCCO)C1CC2C=CC1CC2

Procedure:
Ethyl maleimide (1 mol.), t-butyl 5-norbornene-2-carboxylate (0.5 mol.) and 2-hydroxyethyl bicyclo[2,2,2]oct-5-ene-2-carboxylate (0.5 mol) were dissolved in 50 g to 300 g of tetrahydrofuran (THF), 2 g to 15 g of 2,2′-azobisisobutyronitrile (AIBN) was added thereto, and the resulting solution was reacted at a temperature between 60° C. and 70° C. in a nitrogen atmosphere for 10 hours. After a high molecular weight was achieved by the reaction, the resultant product was precipitated in an ethyl ether or hexane solvent. The gathered precipitate was dried, and the desired poly(ethyl maleimide/t-butyl 5-norbornene-2-carboxylate/3-hydroxypropyl bicyclo[2,2,2]oct-5-ene-2-carboxylate) polymer was obtained at a yield of about 78%.
Reaction SMILES: O1CCCC1.[CH3:6][O:7]/[N:8]=[C:9](/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)\[CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([CH3:34])=[N:26][O:27][C:28]=3[CH2:29][C:30]([O:32]C)=[O:31])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.CO.[OH-].[Li+]>O>[CH3:6][O:7]/[N:8]=[C:9](/[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)\[CH2:10][O:11][C:12]1[CH:36]=[CH:35][C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[C:25]([CH3:34])=[N:26][O:27][C:28]=3[CH2:29][C:30]([OH:32])=[O:31])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: CO/N=C(\COc1ccc(COc2ccc(-c3c(C)noc3CC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO/N=C(\COc1ccc(COc2ccc(-c3c(C)noc3CC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with tetrahydrofuran (5 mL). To the stirred solvent were added Methyl (4-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}-3-methyl-1,2-oxazol-5-yl)acetate (0.47 g, 0.94 mmol), methanol (3 mL) and lithium hydroxide (0.07 g, 0.94 mmol) in water (3 mL). After addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to distill off the solvent; the crude was washed with diethyl ether (5 mL). Water (1 mL) was added and the aqueous layer was acidified with saturated citric acid solution to make pH 6. The aqueous layer was extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white solid (0.32 g, yield: 70.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:27])[CH2:18][O:19]CC2C=CC=CC=2)=[CH:12][CH:11]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:27])[CH2:18][OH:19])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(OC(=O)CO)cc1
Reaction time: 48 h

Procedure:
6-[4-(2-Benzyloxy-acetoxy)-phenoxy]-hexanoic acid methyl ester 19 (15 grams, 38.86 mmol) is dissolved in methanol (100 ml) in a pressure vessel, palladium on carbon (50% wet, 5%, 15 grams) added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 48 hours. The catalyst is removed by filteration and distilled off the methanol. The crude can be purified by column chromatography on silica gel using chloroform as eluant.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].NC(N)=O>>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: NC(N)=O
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Approximately 2000 strains of osmophilic bacteria obtained as described above are cultured in individual microfermentors within a microfermentor array in a medium containing 20% (w/v) D-glucose, 0.1% urea, and 0.5% yeast extract at 30° C. for periods ranging from 12 hours to 5 days. The microfermentors have a working volume of 5 μl and are equipped with means to monitor biomass and oxygen concentration. Each microfermentor delivers oxygen to the interior of the microfermentor vessel via a PDMS aeration membrane. Each strain is introduced into 18 individual microfermentors using access channels. This allows 3 cultures to be terminated at each of 6 time points for each strain. The microfermentor array is maintained in a chamber as described in Example 3, which controls temperature and humidity. Biomass and dissolved oxygen concentration are monitored during the culture period, and data is accumulated using an appropriate software program. After an appropriate culture period (12, 24, 48, 72, 96, or 120 hours), all medium is removed from each microfermentor to be terminated at that time point and analyzed by HPLC to screen for a strain having the ability to produce xylitol.
Reaction SMILES: [OH2:1].[Mn]([O-])(=O)(=O)=O.[K+].[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[CH2:8]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([C:20]([OH:1])=[O:21])=[CH:18][C:17]=1[F:26])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O
Reactant: COc1cc(C=O)cc(F)c1OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 200 ml of water and 6.8 g of potassium permanganate was added dropwise 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde dissolved in 200 ml of acetone at 15 to 20° C., and the resulting mixture was stirred at room temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure to about half volume. To the concentrated solution were added an aqueous sodium hydrogen sulfite solution and dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure, and 4-benzyloxy-3-fluoro-5-methoxybenzoic acid was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:11]O>>[CH3:11][N:1]1[CH2:6][CH:5]=[C:4]([CH:7]=[O:8])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Product: CN1CC=C(C=O)CC1
Reaction time: 1 h

Procedure:
A solution of 4-pyridine carboxaldehyde, O-methyloxime methiodide (32.78 g, 118 mmol) in 150 ml 50% aqueous methanol was added dropwise to a solution of sodium borohydride (7.79 g, 206 mmol) in 150 ml of aqueous 50% methanol keeping the temperature 0° C. ±5° C. After the solution was stirred one hour, some of the inorganic salts were removed by filtration and the filtrate was concentrated to a mass of oily crystals in vacuo. A portion (4.5 g) of this material was partially dissolved in boiling ethyl ether, filtered, and the filtrate treated with hydrogen chloride to give 1,2,3,6-tetrahydro-1-methyl-4-pyridine carboxaldehyde, O-methyloxime, hydrochloride (2.35 g), mp 212°-214° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH:6]([C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.O>[NH2:1][C:2]1[S:3][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:4]=1
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)OCC
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nc(N)sc1C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of thiourea (1.7 g, 22 mmol) and diethyl 2-chloro-3-oxosuccinate (5.0 g, 22 mmol) in absolute ethanol (50 mL) was heated at reflux for one hour. After cooling to room temperature the solvent was removed leaving a white solid. The solid was dissolved in water (100 mL) and the resulting precipitate was filtered and dried (4.6 g, 87%). MS (ES): 245;
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:25][CH:26]=2)[CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12
Reactant: ClCc1ccc(-c2ccccn2)cc1
Reactant: CN1C(=O)c2c(c[nH]c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2c(cn(Cc3ccc(-c4ccccn4)cc3)c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (95 mg, 0.25 mmol) in CH2Cl2 is slowly added TFA and trifluoromethanesulfonic acid (TFMSA). The mixture is stirred at room temperature overnight. Solvents and TFA are removed under reduced pressure. The residue is neutralized and dissolved in DMF, and then purified by a semi-preparative HPLC to give 77 mg of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one. A suspension of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (79 mg, 0.3 mmol), 2-(4-(chloromethyl)phenyl)pyridine (61 mg, 0.3 mmol) and cesium carbonate (192 mg, 0.6 mmol) in anhydrous DMF is stirred at room temperature for 4 h. The mixture is filtered through a 0.2 μL microfilter. The filtrate is purified by a semi-preparative HPLC to give pure product. MS (ESI) m/z 432.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:22][OH:23])([CH2:18][CH2:19][CH:20]=[CH2:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:18]([C:12]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:22][O:23][C:26]([CH3:28])([CH3:27])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCC(CO)(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCCC1(C(=O)OCC)COC(C)(C)N1C(=O)OCc1ccccc1
Yield: 57 %

Procedure:
A solution of the ethyl 2-(benzyloxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate 4 (820 mg, 2.55 mmol) in toluene (10 mL) was treated with 2,2-dimethoxy propane (2 mL) and 4-toluenesulfonic acid (100 mg). The mixture was heated under reflux for 1 h, cooled, concentrated and purified using a combiflash system (12 g silica gel column, eluting with 5-50% of ethyl acetate in heptanes) to give 3-benzyl 4-ethyl 4-(but-3-enyl)-2,2-dimethyloxazolidine-3,4-dicarboxylate (530 mg, 57%). 1H NMR (CDCl3) δ 7.36 (m, 5H), 5.75 (m, 1H), 4.51 (m, 4H), 4.06 (m, 4H) 2.08 (m, 4H), 1.65 (2 s, 6H), 1.13 (t, J=7.1 Hz, 3H). MS found for C20H27NO5 m/z [332 (M+1)].
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:9]([CH2:10][C:11]=1[CH3:12])[C:8](=[O:13])[C:7]([O:14][CH3:15])=[CH:6][C:5]2=[O:16].N#N.Cl>CO>[CH3:1][C:2]1[CH2:3][C:4]2[C:5]([OH:16])=[CH:6][C:7]([O:14][CH3:15])=[C:8]([OH:13])[C:9]=2[CH2:10][C:11]=1[CH3:12]
Reactant: COC1=CC(=O)C2CC(C)=C(C)CC2C1=O
Agent: Cl
Agent: N#N
Solvent: CO
Product: COc1cc(O)c2c(c1O)CC(C)=C(C)C2
Temperature: 25 °C

Procedure:
A solution of 6,7-dimethyl-2-methoxy-4a,5,8,8a-tetrahydronaphthalene-1,4-dione (4.0 g, 18.2 mmol) in MeOH (600 mL) was purged with a stream of N2 for 10 min with stirring at rt. With continued N2 purging, solid K2 CO3 (2.51 g, 18.2 mmol, Baker) was added to the stirred solution. The solution immediately turned yellow. The reaction was allowed to stir for 30 min at rt under N2, after which it was brown. To this there was added a dilute HCl solution (10% concd HCl, 90% H2O, 200 mL) in one portion. The MeOH was removed in vacuo to give a colorless suspension. The suspension was cooled in an ice bath for 20 min. The suspended material was collected by filtration, washed with a dilute acid solution (as above, 3×20 mL) and dried in vacuo to yield a fluffy colorless solid (3.90 g, 98%, pure by 1H NMR analysis (unstable on TLC)); mp 200°-201° C.; 1H NMR (CDCl3) δ1.79 (s, 6H), 3.12 (m, 2H), 3.25 (m, 2H), 3.83 (s, 3H), 4.25 (s, 1H), 5.25 (s, 1H), 6.35 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13].[CH3:25]I.O>CN(C)C=O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]([O:24][CH3:25])([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CI
Reactant: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSC(F)(F)C(Cn1cncn1)(OC)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 60% sodium hydride (0.16 g, 4.0 mmol) in N,N-dimethylformamide (50 ml), 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazole-1-yl)-2-propanol (1.0 g, 3.0 mmol) was added dropwise under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (0.56 g, 3.9 mmol) was then added dropwise to the reaction mixture under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ether. The ether solution was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel column and from the chloroform eluate fraction, 1-[2-(2,4-difluorophenyl)-3-ethylthio-3,3-difluoro-2-methoxypropyl]-1H-1,2,4-triazole (0.81 g, yield: 78%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)/[C:10](=[N:17]\[NH:18][C:19]([NH2:21])=[O:20])/[C:8]1=[O:9])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>CN(C)C=O>[CH:22]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)/[C:10](=[N:17]/[NH:18][C:19]([NH2:21])=[O:20])/[C:8]1=[O:9])([CH3:24])[CH3:23]
Reactant: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)N(CCN1C(=O)/C(=N\NC(N)=O)c2ccccc21)C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
1.10 Grams of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone was suspended in a mixture of ml of dry toluene and 20 ml of dry N,N-dimethylformamide, and the suspension was stirred for 3 hours at 120° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from benzene-hexane to obtain 0.84 g of (Z)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 189°-191° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:18])[NH:16][CH3:17])[CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)(C)(C)C.[ClH:20].O1CCOCC1>>[ClH:20].[NH2:7][C@@H:8]([CH2:9][C:10]1[N:11]=[CH:12][S:13][CH:14]=1)[C:15]([NH:16][CH3:17])=[O:18]
Reactant: CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](N)Cc1cscn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-(1-Methylcarbamoyl-2-thiazol4-yl-ethyl)-carbamic acid tert-butyl ester (248 mg, 0.87 mmol) was dissolved in 4M HCl-dioxane at 0° C. The resulting mixture was stirred for 1 hour at 25° C., concentrated and the residue triturated with ether. Yield, 202 g, 102%; HPLC (70/30) 2.41 minutes (96%);
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl.[Na+].[Cl-]>O1CCOCC1.CO.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:12]([F:15])([F:13])[F:14])[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccnc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccnc(C(F)(F)F)c1C(=O)O
Temperature: 85 °C
Yield: 94.7 %

Procedure:
To a stirred solution of methyl 4-amino-2-(trifluoromethyl)nicotinate (1.97 g, 8.97 mmol) in dioxane/methanol/water (3:2:1 ratio by volume) is added lithium hydroxide (0.365 g, 15.2 mmol). The mixture was heated at 85° C. for 8 hours. The reaction mixture was cooled to room temperature and conc. HCl was added dropwise to adjust the pH to 2-3. Saturated NaCl solution was added. The aqueous layer is extracted with ethyl acetate (12×). The organic layer is washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 1.75 g (95%) of 4-amino-2-(trifluoromethyl)nicotinic acid as a yellow solid. 1H NMR (400 MHz, CD3OD), 8.09 (d, 1H), 6.93 (d, 1H), LC/MS (M+1)=207.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:22]1([O:28][CH2:29][CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.CN(C)C=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:25]2[CH:26]=[CH:27][C:22]([O:28][CH2:29][CH3:30])=[CH:23][CH:24]=2)=[O:9])[CH:10]=1
Reactant: CCOc1ccccc1
Reactant: COc1cc(Cl)c(C(=O)O)cc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxybenzoic acid (4, 15 g, 56.5 mmol) in toluene (72 mL) was added thionyl chloride (8.24 mL, 113 mmol) and N,N-dimethylformamide (0.1 mL). The solution was refluxed at 90° C. for 4 h, cooled to room temperature and evaporated to remove toluene and residual reagent. The obtained acyl chloride was diluted with dichloromethane (240 mL) and added portionwise aluminum chloride (8.3 g, 62.2 mmol) and phenetole (7.2 mL, 56.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight, quenched with 1N HCl (15 mL) and H2O (15 mL). The organic layer was extracted with dichloromethane two times, washed with 1N HCl and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellowish solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:25]1([NH2:32])[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1.C(N(CC)CC)C>CS(C)=O>[NH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:32][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][CH:17]4[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH2:18]4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C[C@H](C)O1
Temperature: 110 °C

Procedure:
The mixture of 5′-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine L (30 mg, 0.08 mmol), trans-1,4-cyclohexanediamine (49 mg, 0.43 mmol) and triethylamine (26 mg, 0.25 mmol) in 1.5 ml DMSO was heated in a reaction vessel at 110° C. in an oil bath for 16 h. Formation of desired product was confirmed by LC/MS. The reaction mixture solution was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Crude compound was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 444.2/446.2 (MH+), retention time=0.54 min.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=4)=[O:20])[CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Yield: 29.6 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(propionylamino)phenyl]carbamate (200 mg, 0.589 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.206 ml, 1.18 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 76.0 mg (29.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(=O)[nH]1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1

Procedure:
The title compound was prepared from 6-methyl-4-(4-trifluoromethyl-phenyl)-1H-pyrimidin-2-one (5.1 g, 20.0 mmol) and phosphoryl chloride (10 mL) according to step 3 of the general procedure I. Obtained as a light brown solid (4.1 g, 75%). MS (ISP) 273.1 [(M+H)+]; mp 82-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCCCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C=CCCCc1ccccc1
Yield: 43.1 %

Procedure:
A solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-5-(5-phenyl-pent-1-ynyl)-phthalazine (280 mg, 0.6 mmole), prepared as described in example 66, in THF (15 ml) was hydrogenated in Parr in the presence of 10% Pd/C (50 mg) for 1 hour, then filtered, brought to dryness and flash chromatographed (eluent: CH2Cl2/CH3OH 98:2). The separated oil was taken up in ethyl ether (5 ml) and crystallised. The yielded crystallised was filtered and dried under vacuum at 40° C. to give 120 mg of the title compound (yield: 43%). m.p.: 121-123° C.