Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(S)C.[H][H].[NH2:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:14])=[C:11]([O:26]C)[CH:10]=1>CN(C=O)C>[ClH:25].[NH2:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:14])=[C:11]([OH:26])[CH:10]=1
Reactant: [H][H]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Product: Cl
Yield: 196.1 %

Procedure:
To a cooled (<10°) stirred suspension of sodium hydride (57.44 g of 60%, 1.436 moles) in DMF (1275 ml) was added dropwise a cold solution of ethanethiol (89.22 g, 1.436 moles) in DMF (250 ml). After hydrogen evolution had ceased 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide (287.0 g, 0.957 moles) (prepared according to U.S. Pat. No. 3,357,978 [1965]) was added and the mixture was heated in an oil bath at 100°-105° for 90 minutes. The solvent was removed in vacuo and the residue partititioned between methylene chloride (800 ml) and water (400 ml). The aqueous layer was washed with another portion of methylene chloride and the combined organic extracts were backwashed with water (150 ml). The combined aqueous phase was cooled in an ice bath and treated with concentrated hydrochloric acid (200 ml). After 20 minutes the precipitate was collected by filtration, sucked briefly on the filter, slurried with methanol ( 500 ml) and again filtered. The product was dried in vacuo to give 302.3 g (98%) of the title compound as a light beige solid, mp 235°-237°.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:28])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][NH:21][CH:22]=2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:26]([O:25][C:23]([C:19]1[C:18](=[O:28])[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)=[CH:22][N:21]([CH2:2][C:3]([OH:5])=[O:4])[CH:20]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)O)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl bromoacetate (341 μl) was added to a suspension of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (400 mg) and cesium carbonate (998 mg) in DMF (8 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted by adding ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure. Dichloromethane (15 ml) and TFA (0.59 ml) were added to the residue at room temperature. The reaction mixture was stirred at room temperature for two hours. TFA (1.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. TFA (4.00 ml) was added to the reaction mixture at room temperature. The reaction mixture was stirred overnight. Water was added to the reaction mixture, and the organic layer was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=19:1->17:3 (v/v)] to give 320 mg of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:20]([CH3:19])[CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccnc2)c1C#N
Reactant: Cc1ccc(CN)cc1C
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3cccnc3)c2C#N)cc1C

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-3-yl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 331 (M+H+, 100).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[C:20]2[CH2:26][N:2]1[C:28]([C:30]2[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3n[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indazole-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 510.13 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])C)(C)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:13][NH:14][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1ccccc1NS(C)(=O)=O
Reaction time: 0.83 h
Yield: 51.9 %

Procedure:
At 0° C., trifluoroacetic acid (6 ml) was added to a solution of N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (870 mg, 2.6 mmol) in dichloromethane (6 ml). The reaction mixture was stirred for 50 min. Dichloromethane (24 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (34 ml) was added. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash crhomatography on silica (60 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 308 mg of N-(2-(2-(methylamino)ethyl)phenyl)methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:11]1[C:12]([NH2:14])=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:10]=1
Reactant: BrBr
Reactant: Nc1cnc(-c2ccncc2)c(-c2cccc(F)c2)n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc(-c2cccc(F)c2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.5 %

Procedure:
To a solution of 6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2-ylamine (Example 1, 70 mg, 0.26 mmol) in chloroform (4 mL) at 0° C. was added pyridine (22 μL, 0.27 mmol) and bromine (14 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 24 h, chloroform (20 mL) was added, the organic layer was washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol 95:5) to provide the title compound as a red solid (22 mg, 24%).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C1COCC1>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)O)cc2)c(O)c2ccccc21
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)c(O)c2ccccc21
Reaction time: 8 h

Procedure:
A solution of 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoic acid (41 mg, 0.1 mmol) in THF is cooled to 0° C., and benzyl alcohol (21 mg, 20 μl, 0.2 mmol) is added, along with EDCI (19 mg, 0.1 mmol) and dimethylaminopyridine (3 mg, 0.02 mmol). The reaction mixture is left to stir overnight. The organic phase is washed with water and evaporated under reduced pressure. The crude product is purified by column chromatography, using 4:1 petroleum ether: ethyl acetate, with a yield of 30 mg (60%). 1H NMR (DMSO): δ 8.16 (d, J=8 Hz, 1H), 8.04 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 3H), 7.68 (d, J=8 Hz, 1H), 7.46-7.25 (m, 6H), 7.38 (m, 1H), 5.30 (s, 2H), 4.28 (bs, 2H), 1.59 (bs, 2H), 1.41-1.15 (m, 6H), 0.84 (bs, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C:10]2=[C:9]1[CH3:26])=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([CH:10]2[CH:9]1[CH3:26])=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:20])[F:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C2c3cccc(C(F)(F)F)c3C(=O)N2CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1C2c3cccc(C(F)(F)F)c3C(=O)N2CCN1C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-3,4-dihydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (0.20 g, 0.54 mmol) in methanol (10 mL) was added palladium on carbon (20 mg, 10 wt′; Aldrich). The resulting mixture was degassed (vacuum then argon, ×3) and subjected to a hydrogen atmosphere (60 psi) for 12 hr. The mixture was then filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (SiO2, 0-50% ethyl acetate in hexanes) to afford N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-1-methyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (0.19 g, 94%) as a white solid. MS (ESI) 371 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][Mg]Cl.[C:24](Cl)(=[O:27])[O:25][CH3:26].O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][N:13]([C:24]([O:25][CH3:26])=[O:27])[CH:14]([CH2:19][CH2:18][C:17]([CH3:23])([CH3:22])[CH3:16])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)CC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N1C=CC(CO[Si](C)(C)C(C)(C)C)=CC1CCC(C)(C)C
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
4-((tert-Butyldimethylsilyloxy)methyl)pyridine (5.58 g, 25 mmol) (from reference compound 4, step 1) was dissolved in dry THF (50 mL) under nitrogen and the mixture cooled to −15° C. (3,3-Dimethylbutyl)magnesium chloride (0.5 M in THF) (50 mL, 25 mmol) was added dropwise during 20 min to yield a yellow solution which was stirred at −15° C. for 30 min. Then, methyl carbonochloridate (2.5 mL, 32 mmol) was added during 1 min. The reaction was continued at −15° C. for 30 min and then the mixture was cooled to −60° C. After 2 h the temperature had reached room temperature. Water (20 mL) was added and the solvent evaporated. The aqueous phase was extracted with DCM (×2) and the combined organic phase passed through a phase separator. The solvent was evaporated to yield a yellow oil. The residue was purified via Biotage (0=>10% EtOAc in heptane) to yield methyl 4-((tert-butyldimethylsilyloxy)methyl)-2-(3,3-dimethylbutyl)pyridine-1(2H)-carboxylate (3.67 g, 44%) as a colourless oil. MS m/z 368 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:16]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[N:15]1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.O.[Cl-].[Na+]>[CH2:22]([O:21][C:19]([C:17]1[C:16]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:33])([F:34])[F:35])[CH:26]=2)=[N:15][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:12])([F:13])[F:11])=[CH:9][C:4]=2[NH2:1])[N:18]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])nc1Oc1cccc(OC(F)(F)F)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2N)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 2-[2-nitro-4-(trifluoromethyl)phenyl]-5-[3-(trifluoromethoxy)phenoxy]-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step F, 0.76 g, 1.5 mmol) in acetonitrile (30 mL) was added a solution of sodium hydrosulfite (1.31 g, 7.5 mmol) in water (20 mL). The mixture was stirred at 23° C. for 2.5 h. The reaction mixture was diluted with saturated aqueous sodium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the title compound (0.70 g) as a pale yellow solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)=[O:31]>>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]2[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:21][CH:20]=1)=[O:31]
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Reactant: O=C(NCCCCO)c1cc2ccccc2o1
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCCNC(=O)c2cc3ccccc3o2)cc1
Yield: 51 %

Procedure:
The product of Example 2 (0.40 g, 1.24 mmol) was coupled to N-(4-hydroxybutyl)-1-benzofuran-2-carboxamide, prepared according to Example 17, (0.29 g, 1.24 mmol) using the procedure of Example 3 to provide 0.34 g (51% yield) of an off white powder. MP>200° C.; 1H NMR (DMSO-d6): δ 1.35-1.62 (m, CH2, CH2), 1.9 (s, CH3), 3.20 (s, CH3), 3.32-3.41 (m, CH2, CH2), 7.0-7.1 (m, 4 Ar H), 7.35 (t, 1 Ar H), 7.45 (t, 1 Ar H), 7.54 (s, 1 Ar H), 7.65 (d, 1 Ar H), 7.77 (d, 1 Ar H), 7.92 (m, 3 Ar H) 8.8 (t, NH). Electrospray Mass Spec: m/z 537.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[NH:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[CH2:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C>[CH2:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[NH:6][CH2:5]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ClCc1ccccc1
Reactant: Nc1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC(CN1NCc2cc(NCc3ccccc3)ccc21)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of (5-Amino-2H-indazol-1-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.065 g, 0.17 mmol) in acetonitrile (1 ml) was slowly added N,N-Diisopropylethylamine (0.033 ml, 0.19 mmol) at 0° C. and the solution was stirred for 30 min in the same condition. Benzylchloride (0.024 g, 0.19 mmol) was added to the solution, which was then stirred at room temperature for 2 hours and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound. (Yield 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[N+:6]=1[O-:7].[H-].[Na+].[CH3:14]I.Cl>O.CN(C)C=O>[CH3:14][O:7][N:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: Cc1[nH]c2ccccc2[n+]1[O-]
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COn1c(C)nc2ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of 7.8 g (0.53 mole) of 2-methylbenzimidazole N-oxide [Chem. Pharm. Bull., 11, 1375 (1963)]in 50 ml of dimethylformamide was added 2.53 g (0.053 mole) of 50% sodium hydride in oil over a period of 5 minutes. After stirring 15 minutes, 3.33 ml (0.053 mole) of methyl iodide was added over a 15-minute period and the reaction mixture allowed to stir at room temperature for 3 hours. The reaction was poured into water, the pH adjusted to 2 with 12N hydrochloric acid and the impurities extracted with ethyl acetate. The pH was adjusted to 12 with 6N sodium hydroxide solution and the product extracted with ethyl acetate (3×100 ml). The extracts were combined, dried over magnesium sulfate and evaporated under a nitrogen stream.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:15][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH:17]=[CH2:18])[CH:3]=1)[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)c2c(c1)C(C)(C)CCC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(OC)cc2c1C(=O)CCC2(C)C
Temperature: 91 °C
Yield: 73.8 %

Procedure:
A solution of 8-bromo-6-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 154, 2.83 g, 10 mmol) and tributyl(vinyl)tin (3 mL, 10 mmol) in anhydrous N,N-dimethyl formamide (30 mL) was sparged with argon and treated with tetrakis(triphenylphosphine)palladium (0) (0.3 g, 0.26 mmol). The resulting reaction mixture was heated to 91° C. for two days at the end of which it was cooled to ambient temperature, diluted with water and extracted with diethyl ether (×2). The combined organic phase was washed with water (×1), and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated to a pale yellow oil. Flash chromatography using 15% ethyl acetate in hexane as the eluent afforded the title product (1.7 g, 73%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:21])[CH:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:21][C:28](=[O:29])[C:24]3[CH:25]=[CH:26][CH:27]=[N:22][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: C[C@H](Oc1ncc(N)cc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(O)c1cccnc1
Product: C[C@H](Oc1ncc(NC(=O)c2cccnc2)cc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 42g, using 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (example 420 and 3-pyridine carboxylic acid (CAN 59-67-6) as starting materials; MS (EI) 422.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[C:6]([N:8]1[C@@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11][CH2:12][C@@H:13]1[CH3:14])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-6-methyl-2-n-pentyl-1,2,3,4-tetrahydropyridine (1.0 g, 3.74 mmol) in 250 mL of CH2Cl2 was added sodium cyanoborohydride (1.41 g, 22.43 mmol). After being stirred 15 minutes at room temperature, the heterogeneous solution was cooled to −42° C. and TFA (2.9 mL, 37.4 mmol) was added slowly dropwise. After being stirred for 4 h at −42° C., the cold bath was removed, and the reaction mixture was immediately quenched with 200 mL of a saturated aqueous NaHCO3/THF mixture (50:50). The aqueous phase was extracted with CH2Cl2 (2×70 mL) and the combined organic extracts were washed with water and brine. The organic phase was dried with K2CO3, filtered through Celite, and evaporated to give crude product. Column chromatography using 5% EtOAc in hexanes gave 0.8 g (70%) of the product which was homogeneous by TLC analysis. 1H NMR (300 MHz) d 3.92-3.81 (m, 1H), 3.69-3.80 (m, 1H), 1.91-1.21 (m, 26H), 0.90-0.86 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].CO>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:22][C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[F:12])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: Clc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
4-Chloropyridine-2-carboxylic acid methyl ester (30 g) and 2-fluoro-4-nitrophenol (41.2 g) were dissolved in chlorobenzene (24 ml), followed by stirring under a nitrogen atmosphere at 120° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature, methanol (100 ml) was added, and stirred for 30 min. The solvent was removed under reduced pressure, then the resultant residue was partitioned between ethyl acetate (300 ml) and a 1N aqueous solution of sodium hydroxide (150 ml). The separated organic layer was washed with a 1N aqueous solution of sodium hydroxide (100 ml) and brine (150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, ethanol (200 ml) was added to the resultant residue, followed by stirring for 30 min. The solid was collected by filtration and the filtrate was purified by silica gel column chromatography (YMC, SIL-60-400/230W, eluent; heptane:ethyl acetate=1:1). Fractions containing the target compound were concentrated under reduced pressure, the resultant solid was combined to the solid above to provide 4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester as a pale brown solid (20.0 g, 40.0%).