Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][C:38]=3[O:51][CH3:52])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][C:38]=3[O:51][CH3:52])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3OC)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3OC)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-methoxybiphenyl-2-carbonitrile (1.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (20 mL). N,N′-Carbonyldiimidazole (0.52 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.48 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.95 g, 72%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:27]=[CH:26][C:25]([OH:24])=[CH:30][CH:29]=4)[CH2:36][CH2:35]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
DIPEA (52.4 mL, 300.84 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (44.6 g, 200.56 mmol) and 1-(4-hydroxyphenyl)piperazine (39.32 g, 220.61 mmol) in DMF (450 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, then evaporated to dryness and partitioned between DCM (2 L) and water (1 L) containing methanol (250 mL) to aid solubility. The insoluble material was collected by filtration, washed with methanol and dried to give the desired product. The organic filtrate was separated from the aqueous, then washed with saturated brine (500 mL), dried over MgSO4 and evaporated to a brown gum. This was triturated with ether, the resulting solid was collected by filtration, washed with DCM followed by methanol, combined with the previous precipitate and dried to afford 4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenol (63.8 g, 87%) as a solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[O:12])=[CH:7][N:6]=1)=O.COC([C:17]1[CH:22]=[N:21][C:20](C(Br)Br)=[CH:19][N:18]=1)=O.[CH2:26](O)[CH3:27]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[CH:5]([N:18]1[CH2:17][CH2:22][N:21]([C:11]([C:8]2[CH:7]=[N:6][C:5]([CH2:3][N:6]3[CH2:27][CH2:26][CH2:11][CH2:8][CH2:7]3)=[CH:10][N:9]=2)=[O:12])[CH2:20][CH2:19]1)([CH3:10])[CH3:3]
Reactant: COC(=O)c1cnc(C=O)cn1
Reactant: CCO
Reactant: COC(=O)c1cnc(C(Br)Br)cn1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2cnc(CN3CCCCC3)cn2)CC1
Temperature: 80 °C

Procedure:
5-Formyl-pyrazine-2-carboxylic acid methyl ester. A solution of 5-dibromomethyl-pyrazine-2-carboxylic acid methyl ester (1.00 g, 3.23 mmol) in a mixture of ethanol (20 mL) and THF (10 mL) was heated to 80° C. A solution of silver nitrate (2.20 g, 12.9 mmol) in H2O (4 mL) was added. The reaction mixture was heated at 80° C. for 1.25 h and was filtered while hot. The filtrate was concentrated to yield the title compound (1.36 g). This material was carried to the next step without purification.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=1)[CH3:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Ethyl 2-chloro-5-fluoronicotinate (5.09 g, 25 mmol, see reference J. Med. Chem., 1993, 36(18) 267–88) and 3,4-dichlorophenol (6.11 g, 37.5 mmol) were dissolved in 1,4-dioxane and the solution was purged with argon. Anhydrous caesium carbonate (12.21 g, 37.5 mmol) was added and the mixture was heated under reflux for 17 hours. The reaction mixture was partitioned between water (300 ml) and ethyl acetate (300 ml). The aqueous layer was acidified to pH 3 by addition of 2M hydrochloric acid and the phases were separated. The aqueous layer was extracted with ethyl acetate (2-fold 100 ml) and the combined organic solutions were dried over magnesium sulphate and concentrated in-vacuo to give a red oil. The material isolated was redissolved in ethyl acetate and was washed with 5% potassium carbonate solution (2-fold 200 ml), 0.5 M sodium hydroxide solution (2-fold 200 ml) and saturated sodium hydrogen carbonate solution (100 ml). The organic phase was dried over magnesium sulphate and concentrated in-vacuo. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (4:96) to give 2-(3,4-dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester as a colourless oil that crystallised on standing (4.95 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[N:14]=[C:13]([CH2:15]Cl)[CH:12]=[CH:11][N:10]=2)[N:4]=1.[NH:17]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[C:34](=[O:37])([O-:36])[O-].[Na+].[Na+]>C(#N)C>[C:30]([O:29][C:27]([CH2:26][N:17]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[N:14]=[C:13]([CH2:15][N:17]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:26][C:34]([O:36][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:37])[CH:12]=[CH:11][N:10]=2)[N:4]=1)[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccnc(-c2nccc(CCl)n2)n1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1ccnc(-c2nccc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n2)n1

Procedure:
4,4'-Bis(chloromethyl)-2,2'-bipyrimidine (18.0 mg, 0.0793 mmoles), di-t-butyl iminodiacetate (76.3 mg, 0.31 mmoles), sodium carbonate (210 mg) and acetonitrile (3 ml) were refluxed overnight. The mixture was filtered, the solvent was evaporated and the product was purified by flash chromatography (silica, 0-5% methanol/chloroform).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][O:4]1)=[CH2:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[H][H]>C(O)CCC>[CH2:5]1[O:4][CH:3]1[CH2:1][CH3:2].[CH:7](=[O:6])[CH2:8][CH2:9][CH3:10]
Reactant: C=CC1CO1
Reactant: [H][H]
Reactant: C1CCOC1
Solvent: CCCCO
Product: CCC1CO1
Product: CCCC=O

Procedure:
In an autoclave having a capacity of 50 ml, the solution to be hydrogenated comprising 2.5 g of vinyloxirane and 22.5 g of tetrahydrofuran was admixed with 0.5 g of catalyst No. 1 without prior activation with hydrogen and hydrogenated with hydrogen at 25° C. and 40 bar for 8 hours while stirring. At a conversion of 100%, 91.7 mol% of 1,2-butylene oxide, 1.0 mol% of n-butyraldehyde and 2.6 mol% of n-butanol were obtained. Examples 3-22
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].[H-].[Na+].[CH3:8][O:9][C:10](=[O:15])[C:11](Br)([CH3:13])[CH3:12].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:8][O:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH:1]([C:4]#[N:5])[C:2]#[N:3]
Reactant: COC(=O)C(C)(C)Br
Reactant: N#CCC#N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(C#N)C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.9 %

Procedure:
In THF (91 ml), 3 g (45.411 mmol) of malonic acid dinitrile was slowly added to 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil). Then 5.876 ml (45.411 mmol) of methyl-2-bromo-2-methylpropanoate was added and it was stirred overnight at RT. Then a further 5.876 ml (45.411 mmol) of methyl-2-bromo-2-methylpropanoate was added and it was heated overnight to 50° C. Then once again, 1.762 ml (13.623 mmol) of methyl-2-bromo-2-methylpropanoate was added and it was heated for a further 4 h to 50° C. Saturated aqueous sodium hydrogen carbonate solution was then added to the mixture and it was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness. 8.9 g of raw product was obtained, and was purified by silica gel chromatography (cyclohexane-ethyl acetate 4:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[O:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[N:15]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:16])=[O:5])C.C[O:27][C:28]([C:30]1[N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][C:33]2=[N:32][C:31]=1N(C(=O)C1C=CC=C(Cl)C=1)C)=[O:29].[OH-].[Na+]>CO.O1CCOCC1.O>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([N:15]([CH3:16])[C:7]1[N:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:6]=1[C:4]([OH:5])=[O:3])=[O:25].[N:32]1[CH:31]=[C:30]([C:28]([OH:29])=[O:27])[N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][C:33]=12
Reactant: CCOC(=O)c1c(N(C)C(=O)c2cccc(Cl)c2)nc2n1CCCC2
Reactant: COC(=O)c1c(N(C)C(=O)c2cccc(Cl)c2)nc2n1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)O)CCCC2
Product: O=C(O)c1cnc2n1CCCC2
Temperature: 25 °C

Procedure:
2-[(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester and 2-[(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid methyl ester (1.0 mmol together) were dissolved in a solution of 16 mL MeOH/dioxan/4 M NaOH in water in a ratio of 15/4/1, and the solution was stirred over night at room temperature. Further NaOH in water (1.5 mL, 6 mmol) was added thereto. After 45 minutes the solvent was removed under vacuum, EtOAc (60 mL) was added thereto and the organic phase was washed with 0.5 M KHSO4 in water (50 mL). The aqueous phase was extracted with EtOAc (60 mL), the combined organic phases were washed with saturated aqueous NaCl solution (80 mL) and dried over sodium sulphate, and the solvent was removed under vacuum. 234 g (70% over two stages) of the desired product 2-(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][C:2]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])([CH3:6])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.C(Cl)Cl.[Br:25]N1C(=O)CCC1=O>>[Br:25][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[Si](CC)(CC)OC(C)(C)C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(C)(C)C(=O)CBr
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a stirred solution of 13 (2.40 g; 10.4 mmol) and triethylamine (2.92 ml; 2.12 g; 21.0 mmol) in methylene dichloride (50 ml) triethylsilyl trifluoromethanesulfonate (2.37 ml; 2.75 g; 10.4 mmol) was added dropwise at 0° C. After 15 min. N-bromosuccinimide (2.05 g; 11.5 mmol) was added and a cooling bath was removed. After 30 min. saturated aqueous solution of NH4Cl (10 ml) and water (50 ml) was added and the mixture was extracted with methylene dichloride (3×100 ml). Organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane—5% ethyl acetate/hexane) to give 1.55 g (5.25 mmol; 50% yield) of 14. 1H NMR (400 MHz, CDCl3) δ 0.64 (6H, q, J=7.9 Hz), 0.97 (9H, t, J=7.9 Hz), 1.41 (6H, s), 4.44 (2H, s); 13C NMR (101 MHz, CDCl3) δ 6.5, 7.0, 27.8, 33.6, 80.4, 206.2; MS (EI) m/z 294 and 296 ([M−Et]+, 24 and 23), 187 (45), 173 (100); exact mass calculated for C9H18O2BrSi ([M−Et]+) 265.0254. found 265.0247.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[OH:5].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[O:5][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 99 %

Procedure:
A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (21.0 g), imidazole (14.25 g), and tert-butyidimethylsilyl chloride (25.0 g) in N,N-dimethylformamide (250 ml) was stirred at room temperature for 18 h. The mixture was poured into water (2.5 l) and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried, and concentrated. The residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless oil (32.63 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:13].[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Clc1ncc(OC[C@@H]2CCN2)cc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To 5-phenyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 67a (380 mg) was added TFA in CH2Cl2 at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO3 to pH 8, then extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2 :MeOH:NH4OH 10:1:0.1 to afford to give the free base of the title compound. MS (CI/NH3) m/z 275 (M+H)+, 277 (M+2H)+. 1H NMR (CDCl3, 300 MHz) δ2.21-2.46 (m, 2H), 3.41-3.50 (m, 1H), 3.73 (dd, J=7.5, 8.0 Hz, 1H), 4.0-4.12 (m, 2H), 4.25-4.35 (m, 1H), 7.26 (d, J=3 Hz, 1H), 7.41-7.48 (m, 5H), 8.09 (d, J=3 Hz, 1H). The base was converted to the salt by treatment with hydrogen chloride saturated EtOH to give the title compound (256 mg). mp 148-150° C. MS (CI/NH3) m/z 275 (M+H)+. 1H NMR (D2O, 300 MHz) δ2.66-274 (m, 2H), 4.06-4.21 (m, 3H), 4.46 (d, J=4.1, 2H), 4.92-5.01 (m, 1H), 7.50-7.59 (m, 5H), 7.60 (d, J=3.0, 1H), 8.20 (d, J=3.0, 1H). Anal. Calcd for C15H15N2OCl·2 HCl: C, 51.82; H, 4.93; N, 8.06. Found: C, 52.10; H, 5.29; N, 7.70. [α]25D=+7.5° (c 0.16, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]C)=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:3]=1[F:22].O.O.[OH-].[Li+]>C1COCC1.CO>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:3]=1[F:22]
Reactant: COC(=O)c1nc(-c2ccc(OC)nc2)c(F)c(N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(C(=O)O)c(OC)c(N)c2F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylate (100 mg, 0.325 mmol) in THF (1.0 mL), MeOH (1.000 mL), and Water (0.500 mL), lithium hydroxide hydrate (60 mg, 1.430 mmol) was added as a solid. The solution was stirred at room temperature for 18 hrs. The reaction solution was then concentrated under vacuum to dryness. The resulting solid was suspended in H2O and the pH was adjusted to 3.8, forming a ppt. The suspension was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to yield 4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylic acid (80.1 mg, 0.273 mmol, 84% yield).). ESIMS for m/z 294 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 3.78 (s, 3H), 3.92 (s, 3H), 6.47 (s, 2H), 6.95 (dd, J=8.7, 0.8 Hz, 1H), 8.15 (ddd, J=8.7, 2.4, 1.1 Hz, 1H), 8.61 (t, J=2.1 Hz, 1H), 13.02 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.78.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH3:30])[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)[C:9]2[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)cc1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Product: CCOC(=O)c1nn(C)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carboxylate (Step 10.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). After purification by silica gel column chromatography, the resulting residue was further purified by preparative HPLC (Gilson gx-281; column: Sunfire C18, 30×100 mm, 5 μm; flow: 30 mL/min; gradient: 5% to 100% B in 20 min; A=0.1% TFA in H2O, B=CH3CN. detection: UV). tR: 3.91 min (HPLC 1); tR: 0.90 min (LC-MS 2); ESI-MS: 415 [M+H]+ (LC-MS 2); Rf=0.46 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:19]([CH3:37])[C:20]([C:35]#[N:36])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[C:19]([CH3:37])[C:20]([C:35]#[N:36])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3ccccc3[N+](=O)[O-])nc2c1C#N
Temperature: 100 °C
Yield: 53.3 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (90 μl, 0.71 mmol) and triethylamine (200 μl) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-5-methyl-2-(2-nitrophenyl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-210) (204 mg, 0.55 mmol). The system was purged with nitrogen, then sealed up, and heated at 100° C. for 1.5 hours. After cooling, the solvent was evaporated away under reduced pressure, then the resulting residue was dissolved in chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform/methanol (98:2, v/v) gave a main product. This was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by filtration to obtain the entitled compound (137 mg, 54%) as a yellow solid.
Reaction SMILES: COC(=O)C1C=CC=CC=1[N+]([O-])=O.[CH3:14][O:15][C:16](=[O:38])[C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:18]=1>O1CCOCC1.[Ni]>[CH3:14][O:15][C:16](=[O:38])[C:17]1[CH:22]=[C:21]([NH2:23])[C:20]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[CH:18]=1
Reactant: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: COC(=O)c1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(N2CCCC2)c1

Procedure:
A solution of 30 g of the nitrobenzoic acid methyl ester obtained according to (b) in 500 ml of dioxane is hydrogenated catalytically in the presence of Raney nickel. After completion of the absorption of hydrogen, the whole is filtered and the filtrate is concentrated. The residue yields, on recrystallisation from methanol, the desired compound in the form of colourless crystals melting at 153°-156° C. in a very good yield.
Reaction SMILES: [OH:1][C:2]1([C:9]([F:18])([F:17])[C:10](O)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.O>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:9]([F:17])([F:18])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12])[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1
Reactant: O=C1CCC(O)(C(F)(F)C(O)(O)C(F)(F)F)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCC(O)(C(F)(F)C(=O)C(F)(F)F)CC1

Procedure:
In 80 ml of toluene was dissolved 10.0 g of 4-hydroxy-4-(2,2-dihydroxy-1,1,3,3,3-pentafluoropropyl)cyclohexanone obtained in <7-1>. The solution was heated under reflux. The water formed was removed, leaving a toluene solution of 4-hydroxy-4-(2-oxo-1,1,3,3,3-pentafluoropropyl)cyclohexanone. Under nitrogen and with stirring at room temperature, this solution was added dropwise to a solution of 3.3 g lithium aluminum hydride in 100 ml tetrahydrofuran. The reaction mixture was stirred at room temperature for 24 hours and then cooled to 5° C. The reaction mixture was combined with 100 ml of ethyl acetate and then with 100 ml of 20% hydrochloric acid. The mixture was stirred at room temperature for 3 hours and then extracted with toluene. Through conventional work-up including washing, drying and concentration, 8.0 g (yield 84%) of the target compound was obtained.