Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[CH:18]=[C:17]([C:26]#[C:27][CH2:28][CH2:29][OH:30])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][C:19]1[CH:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:16]=[C:17]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH:18]=1
Reactant: OCCC#Cc1cc(C#CCCO)cc(-c2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCCCc1cc(CCCCO)cc(-c2ccc(O)cc2)c1

Procedure:
4-[4′-Benzyloxy-5-(4-hydroxybut-1-ynyl)biphenyl-3-yl]but-3-yn-1-ol is dissolved in THF and hydrogenated to completion on a palladium/activated carbon catalyst. The catalyst is filtered off, the filtrate is evaporated in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (1:1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[C:19]([OH:21])=[O:20].O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[O:29]=[C:24]1[CH2:25][CH2:26][C:27](=[O:28])[N:23]1[O:20][C:19]([C:4]1[CH:5]=[CH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:8][C:3]=1[NH2:2])=[O:21]
Reactant: Nc1nc(-c2ncccc2C(F)(F)F)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ncccc2C(F)(F)F)ccc1C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid hydrochloride (11.33 g, 35.44 mmol), N-hydroxy-succinimide (8.15 g, 70.9 mmol), and EDCl (10.19 g, 53.16 mmol) are dissolved in a solution of dry THF (100 mL) and Hunig's base (16.12 g, 125 mmol). The reaction mixture is stirred overnight at room temperature. Ethyl acetate (200 mL) is added and the organic phase extracted with water (3×100 mL) and brine (100 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound as a brown foam.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([C:16]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C(#N)C>[CH2:11]([C:16]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][NH:22][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCCc1ccc(OCCCN)c(CCCCC)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCc1ccc(OCCCNC(=O)Oc2ccccc2)c(CCCCC)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
78.3 g (0.5 mol) of phenyl chloroformate was dissolved in 250 ml of acetonitrile. A mixed solution of 137 g (0.45 mol) of 3-(2,4-diamylphenoxy)propylamine, 69.5 ml of triethylamine and 250 ml of acetonitrile was added dropwise to the solution thus formed in about 3 hours with stirring while the latter was cooled with ice at a temperature of 0° C. After the dropwise addition was finished, the reaction temperature was raised to 25° C. 2 l of ice water was added to the admixture. The admixture was then extracted with chloroform. The chloroform was removed under reduced pressure. Methanol was added to the residual oily matter to obtain 150 g of 3-(2,4-diamylphenoxy)-1-phenoxycarbonylaminopropane.
Reaction SMILES: [OH:1][C:2]([C:10]([F:13])([F:12])[F:11])([CH2:8][CH3:9])[C:3](OCC)=[O:4].O.[NH2:15][NH2:16]>>[OH:1][C:2]([C:10]([F:13])([F:12])[F:11])([CH2:8][CH3:9])[C:3]([NH:15][NH2:16])=[O:4]
Reactant: NN
Reactant: CCOC(=O)C(O)(CC)C(F)(F)F
Solvent: O
Product: CCC(O)(C(=O)NN)C(F)(F)F

Procedure:
The ethyl ester of step 1 (50.04 g, 250 mmol) and hydrazine hydrate (25.03 g, 50 mmol) were heated at 80° C. for 18 h. The excess hydrazine was removed under vacuum and the crude product was filtered through a pad of silica gel with EtOAc-Hexane (ca. 3 L) to furnish the title compound. 1H NMR (400 MHz, acetone-d6): δ 9.7 (s, 1H), 6.10 (s, 1H), 2.25 (m, 1H), 1.85 (m, 1H) and 0.95 t, (3H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:36])[F:37])=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2C(F)(F)F)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2ccccc2C(F)(F)F)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-(2-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.43 min; [M+H]+=526.1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]=[C:28]=[S:29]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[CH2:17][S:18][CH2:19][CH2:20][NH:21][C:28]([NH:27][CH3:26])=[S:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=S
Reactant: NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 36.1 %

Procedure:
There was dissolved 3.0 g (0.0082 mol) of N-[3-[3-(piperidinomethyl)phenoxy]propyl]-2-(2-aminoethylthio)acetamide in 50 ml of chloroform. Thereto was added dropwise a solution of 0.6 g (0.0082 mol) of methyl isothiocyanate in 10 ml of chloroform, and then the mixture was refluxed with heating for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 1.3 g of the titled compound as oily matter.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][CH:10]1[C:20]([O:22]CC)=[O:21])=[O:8])(=O)C.[OH-].[K+]>CO.O>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:11][CH:10]1[C:20]([OH:22])=[O:21])=[O:8]
Reactant: CCOC(=O)C1SC(c2ccccc2)=NN1C(=O)CCSC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1SC(c2ccccc2)=NN1C(=O)CCS
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A solution of the product of step (b) (2.6g) in methanol (20ml) was cooled to 0° under nitrogen and treated dropwise with a solution of potassium hydroxide (1.42g) in water (8ml). The mixture was allowed to warm to room temperature over 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was acidified with 2N HCl and the organic phase separated, washed with water and dried. Evaporation yielded an oil which slowly crystallised to give the title product (0.7g) as white crystals. mp 145°-6°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To 10 mL of a chloroform solution containing 252 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 136 mg of 2-naphtoaldehyde, 50 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 276 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=2:1], to give 279 mg of 7-fluoro-1-(2-(4-((naphthalen-2-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[C:16]([F:18])[N:15]2[N:19]=[C:20]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:21]([C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:23])=[C:14]2[CH:13]=1.CC1C=CC(C(O)=O)=CC=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[C:27]([O:26][C:25]([N:24]([CH3:32])[C:22]([C:21]1[C:20]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:19][N:15]2[C:16]([F:18])=[CH:17][C:12]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]([OH:8])=[O:7])=[CH:13][C:14]=12)=[O:23])=[O:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(F)cc(Cl)cc12
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
3-(3-(tert-butoxycarbonyl)methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid. To a degassed mixture containing tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.060 g, 0.14 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.047 g, 0.18 mmol), sodium carbonate (0.043 g, 0.43 mmol), dioxane (1.2 mL) and water (0.24 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.005 g, 0.004 mmol). The mixture was stirred at 95° C. for 18 h. The mixture was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1 N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.725 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.O1CCCC1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][F:34])[CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1>O>[CH3:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][F:34])[CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:20][CH:21]=1)[CH3:1]
Reactant: CNc1ccc(-c2cc3ccc(OCCF)cc3s2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CN(C)c1ccc(-c2cc3ccc(OCCF)cc3s2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
Potassium carbonate (35 mg, 0.245 mmol) and iodomethane (CH3I, 21 μL, 0.330 mmol) were added to an anhydrous tetrahydrofuran (5 mL) solution having the 2-[4-(N-monomethylamino)phenyl]-6-(2-fluoroethoxy)benzothiophene (1-12, 50 mg, 0.165 mmol) prepared in Example 12 dissolved therein, and stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and water was added. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-[4-(N,N-dimethylamino)phenyl]-6-(2-fluoroethoxy)benzothiophene (1-16, 24 mg, 46%). The obtained target compound 1-16 had a melting point of 183.9-195.9° C., and the following physical data;
Reaction SMILES: [N:1]1([C:6]2[C:7]([C:21]([F:24])([F:23])[F:22])=[CH:8][C:9]([N+:18]([O-])=O)=[C:10]([CH:17]=2)[NH:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:5]=[CH:4][N:3]=[CH:2]1.NC1C=C(C(F)(F)F)C(N2C=CN=C2)=CC=1NCCCCO.[C:47]([OH:52])(=O)[C:48](O)=[O:49].[BrH:53]>C(O)C.[C].[Pd]>[BrH:53].[Br:53][CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:10]2[C:9](=[CH:8][C:7]([C:21]([F:24])([F:23])[F:22])=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:17]=2)[NH:18][C:48](=[O:49])[C:47]1=[O:52]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(-n2ccnc2)cc1NCCCCO
Reactant: O=C(O)C(=O)O
Agent: [Pd]
Agent: Br
Agent: Nc1cc(C(F)(F)F)c(-n2ccnc2)cc1NCCCCO
Solvent: CCO
Product: O=c1[nH]c2cc(C(F)(F)F)c(-n3ccnc3)cc2n(CCCCBr)c1=O

Procedure:
At room temperature, 4-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylanilino)butanol (5.79 g) synthesized in Reference Example 6 was subjected to reduction in ethanol at ordinary temperature using 10% palladium-carbon as the catalyst, thereby converting it into 4-[2-amino-5-(1H-imidazol-1-yl)-4-trifluoromethylanilino)butanol which was subsequently dissolved in 48% hydrobromic acid aqueous solution (50 ml). Then, oxalic acid (2.27 g) was added, followed by heating overnight under reflux. The reaction solution was concentrated under a reduced pressure, and addition of water to the resulting residue followed by concentration was repeated several times. When the residue became a water-insoluble solid, this was collected by filtration, washed with water and then dried under a reduced pressure, and the resulting crude product was recrystallized from DMF-water to give 1-(4-bromobutyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione hydrobromide (2.46 g). The resulting bromobutylquinoxalinedione (2.46 g) and tetra-n-butylammonium bromide (0.15 g) were dissolved in a two layer system solution of chloroform (50 ml), water (50 ml) and DMF (25 ml), and the solution was adjusted to pH 7 by adding 1 N sodium hydroxide. Then, sodium azide (3.12 g) was added, followed by heating overnight under reflux. The organic layer was separated from the reaction solution, washed with water, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. As the remaining solid substance, 1-(4-azidobutyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (1.61 g) was obtained. Next, in an atmosphere of hydrogen, the resulting azidobutylquinoxalinedione (1.30 g) was subjected to reduction under normal pressure in DMF (65 ml) using palladium-carbon as the catalyst. The reaction solution was filtered to collect insoluble matter including the catalyst. This was dissolved in heated DMF, filtered during hot condition and then recrystallized to give 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione (0.82 g).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[OH:11].Cl[C:15]([F:20])([F:19])C([O-])=O.[Na+].[OH-].[Na+].Cl>O.CN(C)C=O>[CH3:1][O:2][N:3]([CH3:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][CH:15]([F:20])[F:19]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CON(C)C(=O)c1cccnc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccnc1OC(F)F
Temperature: 25 °C
Yield: 53.2 %

Procedure:
N-methoxy-N-methyl-2-hydroxynicotinamide (500 mg, 2.76 mmol), sodium chlorodifluoroacetate (505 mg, 3.31 mmol), and sodium hydroxide (132 mg, 3.31 mmol) were added to N,N-dimethylformamide (1.4 mL). The resultant mixture was stirred at 125° C. overnight under an argon atmosphere. The reaction solution was cooled down to room temperature, added with 1N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (chloroform/methanol=9/1). N-methoxy-N-methyl-2-difluoromethoxynicotinamide (341 mg, yield 53%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22]Br)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CCOCC>C1COCC1.CCOC(C)=O.CCCCCCC>[C:14]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22][N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN1CCC(Cc2ccccc2)CC1

Procedure:
A mixture of 4-benzyl-piperidine (876 mg, 5.0 mmol), (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.12 g, 5.0 mmol) and DIPEA (650 mg, 5 mmol) in THF (30 mL) is heated at reflux for 15 h. The solution is poured into ether (150 mL) and extracted with saturated Na2CO3 (2×50 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated to provide a crude oil. Flash chromatography (EtOAc/heptane: 3/2) provides the title compound.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[N:4]1>O.C1COCC1.CO>[NH:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[N:4]1
Reactant: CCOC(=O)Cc1cccc(-c2cn[nH]c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(-c2cn[nH]c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaOH (57 g, 1.43 mol) was added to a solution of ethyl [3-(1H-pyrazol-4-yl)phenyl]acetate (110 g, 0.478 mol) in H2O/THF/MeOH (250 mL/250 mL/250 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the pH was adjusted to 3 to 4 via the addition of 3 M HCl, The solid was collected via filtration and dried to afford [3-(1H-pyrazol-4-yl)phenyl]acetic acid. MS ESI calcd. for C11H11N2O2 [M+H]+ 203. found 203. 1H-NMR (500 MHz, DMSO-d6) δ: 7.94 (s, 2H), 7.41-7.24 (m, 2H), 7.13 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 3.13 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.Cl>O1CCCC1.ClCCl.C(OCC)(=O)C>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7]([C:6]2[C:5]([OH:11])=[N:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)=[O:9])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)cnc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)cnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
5-Chloro-2-hydroxynicotinic acid (174 mg, 1 mmol), 3,5-bis(trifluoromethyl)aniline (275 mg, 1.2 mmol) and pyridine (316 mg, 4 mmol) were dissolved in tetrahydrofuran (20 mL) and dichloromethane (10 mL). Phosphorus oxychloride (0.112 ml, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (100 mL) and 0.2 N hydrochloric acid (100 mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound (183 mg, 47.6%) as a white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Dissolve (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-ol (6.8 g, 27.64 mmol), (prepare according to Stenkamp, D. et al WO 2005103032) in CH2Cl2 (50 mL), and cool to 0° C. Treat the mixture with Et3N (5.0 mL, 35.93 mmol), followed by MsCl (2.4 mL, 30.4 mmol). Stir the mixture at 0° C. for 30 min and then at RT for 1 h. Dilute with CH2Cl2 (100 mL), and wash with H2O (100 mL), and brine (100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 50-70% EtOAc/hexane, to give 8.86 g (97%) of the title compound. MS/ES m/z (79Br) 321.0 [M+H]+.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]2C(=O)OC(C)(C)[O:24][C:23]2=[O:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].Cl>C(Cl)(Cl)Cl.O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]([OH:31])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 100 °C

Procedure:
After adding 2.5 ml of the mixture of formic acid and triethylamine prepared according to Example 1 to 2.94 g (0.01 mol) of 5-(3,4-dimethoxyphenylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (m.p.: 142°-144° C.), the reaction mixture was heated to 100° C. for 2 hours, then cooled down. After the addition of 25 ml of water the pH value was adjusted to 1 by adding concentrated hydrochloric acid, then the mixture was thoroughly shaken with 100 ml of chloroform. After separation the chloroform phase was evaporated under reduced pressure to give a white crystalline product.