Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:31][O:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Cl)=[CH:36][C:35]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]>CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:13][CH2:12][C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:36][C:35]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: OCc1ccc(-c2ccccc2)o1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCc2ccc(-c3ccccc3)o2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
The 5-phenyl-2-hydroxymethylfuran prepared in Example 327B (345 mg, 1.98 mmol) was dissolved in 5 mL of dry DMF and NaH (50 mg, 1.98 mmol) was added followed by 15-crown-5 (436 mg, 1.98 mmol) and the reaction stirred for 5 minutes at ambient temperature. To the reaction was then added 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (659 mg, 2.40 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3×) and brine (3×), dried over Na2SO4, filtered, evaporated and purified by flash chromatography (15% ethyl acetate-hexanes) to give the desired compound (670 mg, 82%) as an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([NH2:17])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].CO[C:20](OC)([CH3:22])[CH3:21]>C(#N)C.C(O)(=O)C.C(Cl)(Cl)Cl>[C:20](=[N:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3])([CH3:22])[CH3:21]
Reactant: CCCc1nc2cnc3ccccc3c2n1N
Reactant: COC(C)(C)OC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCCc1nc2cnc3ccccc3c2n1N=C(C)C
Temperature: 100 °C
Reaction time: 144 h
Yield: 78.8 %

Procedure:
A solution of 2-propyl-1H-imidazo[4,5-c]quinolin-1-amine (4.64 g, 20.5 mmol) in 60 mL of acetonitrile and 15 mL of glacial acetic acid was treated with 2,2-dimethoxypropane (12.6 mL, 103 mmol) and heated to 100° C. under an atmosphere of nitrogen. After 6 d, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in 100 mL of CHCl3 and washed with 10% Na2CO3 (2×25 mL), water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4.30 g of N-isopropylidene-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)amine as a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][OH:21])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH2:20][O:21][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:17])[F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F
Product: COc1ccc(OCCCN(CC2CC2)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(cyclopropylmethyl)(3-hydroxypropyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (APCI) m/z 405 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][Si](C(C)C)(C(C)C)C(C)C)[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1COCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[CH:39])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: CC(C)[Si](C#Cc1cccc2nc(Cn3nc(-c4cccc(O)c4)c4c(N)ncnc43)n(Cc3ccccc3Cl)c(=O)c12)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc2nc(Cn3nc(-c4cccc(O)c4)c4c(N)ncnc43)n(Cc3ccccc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of compound (19) (107 mg, 0.15 mmol) in DMF (0.50 mL) was added tetrabutylammonium fluoride (190 μL of a 1.0 M solution in THF, 0.19 mmol). After 10 min, the reaction mixture was diluted with water (3.0 mL) and cooled to 0° C. for 30 min. The resulting solid was collected by filtration and purified by flash column chromatography, eluting with 4.5% methanol in DCM, to afford the title compound, Example 1, (70 mg, 85%) as a white solid: m/z 534/536 (M+H)+ (ES+); Rt 3.73 min; 1H NMR (500 MHz, DMSO-d6) δ: 4.42 (1H, s), 5.30 (2H, s), 5.77 (2H, s), 6.16 (1H, d), 6.79 (1H, t), 6.84 (1H, dd), 6.89-6.96 (2H, m), 7.04 (1H, t), 7.14 (1H, d), 7.30 (1H, t), 7.70 (1H, d), 7.75 (1H, d), 7.80-7.87 (1H, m), 8.18 (1H, s), 9.67 (1H, s).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C1COCC1>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:24]=[C:23]([Si:20]([CH3:22])([CH3:21])[CH3:19])[N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: C#C[Si](C)(C)C
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 248.0 g, 685.0 mmol) in anhydrous THF (600 mL) was heated with trimethylsilylacetylene (100.9 g, 145.2 mL, 1027.6 mmol, 1.5 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 12 h. When TLC and HPLC/MS showed that the cycloaddition reaction was complete, the reaction mixture was cooled down to room temperature before being concentrated in vacuo. The residue was further dried in vacuo to afford the crude, desired (5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one (1024, 315.1 g, 315.1 g theoretical, 100%) as brown oil, which was directly used in the subsequent reaction without further purification. For 1024: 1H NMR (300 MHz, DMSO-d6) δ 0.01 (s, 9H, SiCH3), 3.67 (dd, 1H, J=6.4, 9.2 Hz), 4.01 (t, 1H, J=5.4 Hz), 4.59 (d, 2H, J=4.9 Hz), 4.91-4.94 (m, 1H), 6.88 (dd, 1H, J=2.4, 8.7 Hz), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.58 (dd, 1H, J=7.5, 8.7 Hz), 7.73 (s, 1H, triazole-H); C15H18FIN4O2Si, LCMS (EI) m/e 461 (M++H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1C(=NO)Cl.Cl.C(=N[OH:22])(Cl)C1C=CN=CC=1.Cl.[C:24](=[N:32][OH:33])(Cl)[C:25]1[CH:30]=[CH:29][CH:28]=NC=1>>[N:2]1[CH:3]=[CH:4][C:5]([C:24]2[CH:25]=[C:30]([CH2:29][CH2:28][OH:22])[O:33][N:32]=2)=[CH:6][CH:7]=1
Reactant: ON=C(Cl)c1ccccn1
Reactant: ON=C(Cl)c1ccncc1
Reactant: ON=C(Cl)c1cccnc1
Agent: Cl
Product: OCCc1cc(-c2ccncc2)no1

Procedure:
By substituting an equimolar amount of picolinoyl chloride oxime hydrochloride or isonicotinoyl chloride oxime hydrochloride for the nicotinoyl chloride oxime hydrochloride employed in the above example, there is obtained the corresponding 3-(2-pyridyl)-5-isozazoleethanol and 3-(4-pyridyl)-5-isoxazoleethanol.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].Br[CH2:20][C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35]3[N:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=3)[CH:30]=[C:31]([CH3:33])[CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:33][C:31]1[CH:32]=[C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])=[N:26][CH:25]=2)[CH:28]=[C:29]([NH:34][C:35]2[N:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:38]=[CH:37][N:36]=2)[CH:30]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CBr)nc2)c1
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CN3CCCC3=O)nc2)c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.6 M, 303 μL, 0.484 mmol) was added to diisopropylamine (67.3 μL, 0.473 mmol) in THF (394 μL) at −78° C. The reaction was warmed to −40° C. and was stirred for 1 hour. The reaction mixture was cooled back to −78° C. and a solution of pyrrolidin-2-one (15.1 mg, 0.177 mmol) in THF (100 μL) was added dropwise. The reaction mixture was warmed to −40° C. and stirred for 1 hour. The reaction mixture was cooled back to −78° C. and a solution of N-{3-[6-(bromomethyl)pyridin-3-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (50.0 mg, 0.118 mmol) in THF (300 μL) was added. The reaction mixture was slowly warmed to room temperature and quenched with saturated aqueous ammonium chloride (1.00 mL) and THF was removed under reduced pressure. The reaction mixture was extracted with dichloromethane and the organic was dried over sodium sulfate and concentration under reduced pressure. The residue was purified by reverse phase prep HPLC (10-80% MeCN in water with 0.5% TFA) to yield 1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}pyrrolidin-2-on. MS APCI calc'd for C22H21F3N5O [M+H]+ 428. found 428. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.78 (d, J=2.0, 1H), 8.04 (dd, J=2.3 Hz, 8.1 Hz, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.38 (d, J=8.1, 1H), 7.27 (d, J=4.9 Hz, 1H), 7.20 (s, 1H), 4.52 (s, 3H), 4.38 (br s, 2H), 3.37 (t, J=7.0 Hz, 2H), 2.31 (t, J=8.1 Hz, 2H), 1.96 (q, J=7.6 Hz, 15.1 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:32]CCl>>[ClH:32].[C:21]([C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(N2CCCNCC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(4-tert-butyl-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (541 mg; 16.3 mmol, prepared in accordance with Example 160) is added a 2:3 mixture of trifluoroacetic acid and dichloromethane (5 mL) and the resulting reaction mixture is stirred at room temperature for 2 hours. All volatiles are then removed under high vacuum and the residue is taken up in a 4 molar solution of hydrochloric acid in dioxane. The solution is allowed to stand over night and the precipitate formed is filtered, washed (diethyl ether) and dried under high vacuum to afford the desired compound (452 mg) which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[O:17][CH3:18])[CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.C(OCC)C.O>[F:19][C:20]([F:22])([F:21])[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[C:10]([O:17][CH3:18])[CH:11]=1)[OH:14]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cc(C=O)ccc1Oc1cccc(F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of 4-[(6-fluoropyridin-2-yl)oxy]-3-methoxy benzaldehyde (300 mg; 1.2 mmol) with trifluoro methyltrimethylsilane (228 μl; 1.46 mmol) in THF (3 ml) under argon at 0° C. was added a molar solution of TBAF in THF (10 μl; 0.012 mmol). The reaction mixture was allowed to stir at rt for 2 h and a molar aqueous solution of HCl was added dropwise (2.5 ml; 2.5 mmol). The reaction mixture was stirred for another 2 h. water and diethylether were added. The aqueous phase was further extracted (2×EtOAc). Combined organic phases were dried over MgSO4, concentrated in vacuo to afford the title compound as a white solid (333 mg; 1.05 mmol; 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16]CC)=O)[C:5]2=[O:19].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=O.[B].[OH-:31].[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([N:8]1[CH2:9][CH2:4][O:31][CH2:6][CH2:7]1)=[O:16])[C:5]2=[O:19]
Reactant: O=C1Cc2ccccc2C1
Reactant: CCOC(=O)c1cn(CC)c2ncc(N)cc2c1=O
Reactant: [OH-]
Agent: [B]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)N2CCOCC2)c(=O)c2cc(NC3Cc4ccccc4C3)cnc21
Temperature: 42.5 °C

Procedure:
Other Alternative Methods. To a suspension of ethyl 6-amino-1-ethyl-4-oxo-1,8-naphthyridine-3-carboxylate in a solvent specified in Table 1 was added acetic acid and the mixture was stirred until all solids went into solution (may need to warm up to 40-45° C.). 2-Indanone was added to reaction mixture and stirred to completion of imine formation (indicated by disappearance of starting material in LCMS) (˜30 min to 1 h). Boron reducing agent (as listed in Table 1) was added to reaction mixture and stirred vigorously to completion of imine reduction (disappearance of imine in LCMS). The reaction mixture was transferred to a beaker, diluted with ethyl acetate, added an ice-cooled aqueous sodium hydroxide solution (1.0 M) (enough to quench almost 90% of acetic acid) and then further basified with solid sodium bicarbonate to pH 7-8. The organic layer was separated, washed with brine, dried over MgSO4 and evaporated under reduced pressure to dryness. Where specified in Table 1, the crude was passed through a plug of silica gel with increasing gradient of EtOAc in DCM to offer the required product as dark yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.O1CCCC1.[CH:16]([S:19]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])(=[O:21])=[O:20])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[S:19]([CH:16]([CH3:18])[CH3:17])(=[O:21])=[O:20])[N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: COc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(Cl)nc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a mixture of 2,4-dichloro-6-methoxy-1,3,5-triazine (370 mg) and tetrahydrofuran (10 mL), a mixture of 2-(isopropylsulfonyl)aniline (400 mg), N-ethyl-N-isopropylpropane-2-amine (0.72 mL) and tetrahydrofuran (5 mL) was added and stirred overnight at room temperature and further stirred at 70° C. for 7 hours. The reaction mixture was cooled on ice and diluted with water (60 mL). The precipitated solid was collected by filtration, purified by silica gel column chromatography (eluent; chloroform) and then washed with hexane to give 4-chloro-N-[2-(isopropylsulfonyl)phenyl]-6-methoxy-1,3,5-triazine-2-amine (200 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)(O)[O-:12].[Na+].[N+]1([O-])C=CC=CC=1>C1(C)C=CC=CC=1>[O:12]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCCCBr
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][n+]1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCC=O
Reaction time: 9 h
Yield: 48.7 %

Procedure:
Ethyl 5-bromopentanoate (42 g), sodium bicarbonate (34 g) and pyridine N-oxide (38 g) in toluene (250 ml) are heated together under reflux in an atmosphere of nitrogen with vigorous stirring for 9 hours. After cooling, the product is partitioned with water (400 ml). The toluene layer is separated and the aqueous layer is extracted with a further amount of toluene (100 ml). The combined toluene extracts are dried over magnesium sulphate and the toluene removed by fractional distillation. The residue is distilled under vacuum to give ethyl 5-oxopentanoate as a colourless oil (14.1 g), m.s. M+ 144.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:10]([C:17]#[N:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-:19].[K+]>>[CH3:1][C:2]1[C:7]([C:8]2[N:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:10]([C:17]([NH2:18])=[O:19])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1-c1cc(C#N)c2n1CCCC2
Reactant: [OH-]
Agent: [K+]
Product: Cc1ncccc1-c1cc(C(N)=O)c2n1CCCC2
Yield: 87.2 %

Procedure:
3-(2-Methyl-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is prepared as described in Example 11, from 23.3 g of 3-(2-methyl-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 33 g of potassium hydroxide. 21.85 g of 3-(2-methyl-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide are thus obtained in the form of a white solid melting at 244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:39])[N:33]=[C:34](SC)[NH:35][CH:36]=2)=[CH:26][N:25]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:34]2[NH:35][CH:36]=[C:31]([CH2:30][C:27]3[CH:26]=[N:25][C:24]([O:23][CH3:22])=[N:29][CH:28]=3)[C:32](=[O:39])[N:33]=2)=[CH:8][CH:7]=1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)c(Cl)c4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 50 h
Yield: 20.2 %

Procedure:
2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.322 mmol, 0.95 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 50 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.064 mmol, yield: 20%, UPLC-MS/UV: [M+H]+=517.97; rt: 11.53 mins; purity: 90%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.92 (t, J=7.76, 2H), 3.51 (s, 2H), 3.59-3.70 (m, 2H), 3.94 (s, 3H), 5.33 (br.s., 1H), 6.86 (dd, J=9.07, J=2.01, 1H), 6.96-7.03 (m, 2H), 7.23-7.31 (m, 3H), 7.58 (d, J=8.82, 1H), 7.67 (s, 1H), 8.39 (s, 2H)
Reaction SMILES: [CH2:1]([C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([C:10]#[N:11])[C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H][H]>C(OCC)C>[CH2:12]([C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][NH2:9])[CH2:10][NH2:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(C#N)(C#N)CCCCCC
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(CN)(CN)CCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
2,2-Dihexylpropanedinitrile (22.0 g, 94 mmol) dissolved in dry diethyl ether (100 ml) was added slowly to a suspension of lithium aluminium hydride (8.7 g, 0.23 mol) in dry diethyl ether (250 ml) under nitrogen. Upon complete addition, the mixture was heated under reflux using a water bath for 1 h and then stirred at room temperature for 24 h. Water was carefully added to the reaction mixture with cooling of the flask in an ice bath, until no more hydrogen was evolved. The reaction mixture separated into two layers and the ether layer was decanted from the aqueous layer, washed with water, and dried with anhydrous magnesium sulphate. The ether was evaporated to yield a viscous oil that was distilled under reduced pressure to yield 2,2-dihexylpropane-1,3-diamine as a colorless liquid (11.2 g, 49%) b.p. 138°-142° C./0.7 mm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:14]1[C:15]([O:23][CH3:24])=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=1)[CH:19]=O)([CH3:13])[CH3:12]>>[CH:11]([C:14]1[C:15]([O:23][CH3:24])=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=1)[CH:19]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10])([CH3:13])[CH3:12]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: O=C1Cc2ccccc2N1
Product: COc1cc(C)c(C=C2C(=O)Nc3ccccc32)cc1C(C)C

Procedure:
2-Oxindole was condensed with 5-isopropyl-4-methoxy-2-methylbenzaldehyde using method B to give 0.25 g of 3-(5-Isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid which was reduced using method E to give 2 g (100%) of 3-(5-isopropyl-4-methoxy-2-methylbenzyl)-1,3-dihydroindol-2-one as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2.C([O-])(O)=[O:17].[Na+]>CC(C)=O.O>[F:15][C:4]1[C:3]([CH2:2][OH:17])=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ccc(F)c(CO)c2n1
Yield: 73.2 %

Procedure:
A suspension of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (25 g, 92.56 mmol) in acetone (360 mL) and water (460 mL) was treated with NaHCO3 (12.74 g, 151.64 mmol, 1.6 eq). The mixture was heated to reflux overnight. After cooling, the volatiles were removed in vacuo and the residue was partitioned between EA (300 mL) and water (100 mL). The aq. layer was extracted once with EA (250 mL) and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 3:1) to afford the title alcohol as a yellowish solid (14.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[N+:19]([O-])([O-:21])=[O:20].[Na+]>>[NH2:1][C:2]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2.0 g (13.3 mmol) of 6-amino-3H-benzoxazol-2-one [J. Chem. Soc., 321 (1938)] in 20 ml of trifluoroacetic acid 1.2 g (14.1 mmol) of sodium nitrate is added below 20° C. The reaction mixture is stirred at room temperature overnight, then concentrated. The residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent to yield 2.50 g (96%) of the title compound. Mp.: 198° C. (toluene—methanol).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([Br:10])[CH:4]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[Br:10][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.26 g of sodium hydride at 50% in oil were added at 0° C. to a solution under an inert gas atmosphere of 50 g of p-bromophenol in 320 ml of dimethylformamide and after the mixture was stirred for 30 minutes at 0° C., then 37.7 ml of benzyl bromide were added. The mixture was stirred for 2 hours 30 minutes, allowing the temperature to rise to 20° C., and then the reaction mixture was poured into ice-cooled water. The precipitate was filtered off and dried to obtain 73.35 g of the expected product with an Rf: 0.85 (thin layer chromatography, support: silica, eluant: cyclohexane/ethyl acetate 7/3).