Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[O:2][CH3:1])[O:10][N:9]=1)=[O:13]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccccc2OC)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1Cc1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Yield: 43.8 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2-methoxybenzyl)-1,2,4-oxadiazole-3-carboxylate (0.113 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.078 g (44%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.C([O-])([O-])=O.[K+].[K+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N+:36]([CH2:38][C:39]([O:41][CH3:42])=[O:40])#[C-:37]>CN(C=O)C>[C:9]([O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]1[O:6][CH:37]=[N:36][C:38]=1[C:39]([O:41][CH3:42])=[O:40])([CH3:12])([CH3:11])[CH3:10]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)(C)OC(=O)CCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
To an ice-cooled mixture of mono-tert-butyl succinate (5.0 g, 28.7 mmol) and K2CO3 (15.9 g, 114.8 mmol) in DMF (40 mL) were added diphenylphosphoryl azide (11.06 g, 40.2 mmol) and methyl isocyanoacetate (3.41 g, 34.4 mmol). After being stirred at room temperature for 16 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica-gel, 9:1-3:7 hexane/ethyl acetate) to give the title compound (6.20 g) as a brown oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:18]1[C:22]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])=[CH:21][N:20]=[CH:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[O:18]1[C:22]([C:23]2[CH:24]=[C:25]([NH:26][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)[CH:27]=[CH:28][CH:29]=2)=[CH:21][N:20]=[CH:19]1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1cccc(-c2cnco2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3cccc(-c4cnco4)c3)n2)c1
Yield: 25.8 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 3-(1,3-oxazol-5-yl)aniline (56.1 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as for Method L and a combination of column chromatography and preparative TLC afforded 23 mg of pure title compound. Yield: 25.8%. 1H NMR (250 MHz, DMSO-d6) δ 2.08 (s, 3H), 7.36 (d, 1H, 8.0 Hz), 7.48 (t, 2H, 8.3 Hz), 7.61 (s, 1 H), 7.65 (d, 1 H, 8.4 Hz), 7.82 (d, 2 H, 7.3 Hz), 8.23 (s, 1 H), 8.39 (bs, 2 H), 8.46 (s, 1 H), 8.47 (s, 1 H), 9.82 (s, 1 H), 10.09 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.0, 113.4, 117.1, 117.3, 118.3, 120.3, 121.3, 121.8, 127.9, 129.3, 129.8, 130.3, 133.7, 137.0, 139.9, 141.4, 147.9, 150.8, 151.3, 151.7, 168.5; m/z 372.2 [(M+H)+, calcd for C21H17N5O2 371.1].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:37][N:38]([CH3:42])[C:39]([NH2:41])=[S:40]>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:40][C:39]([N:38]([CH3:42])[CH3:37])=[N:41][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(N)=S
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (2.0 g, 4.72 mmol) in 25 mL DMA was added NBS (0.88 g, 4.95 mmol). The mixture stirred at rt for 30 min. N,N-Dimethylthiourea (0.6 g, 5.66 mmol) was added and the mixture heated to 40° C. overnight. The mixture was poured into 300 mL ice water and the crude product was collected by filtration. The crude product was then purified by flash chromatography to give the title compound of Step A (0.6 g, 1.18 mmol, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.09 (s, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.68 (s, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.22 (ddd, J=17.3, 8.5, 8.2 Hz, 5H), 6.47 (d, J=5.5 Hz, 1H), 3.12 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][OH:40].[ClH:41]>CN(C)C=O.C(OCC)C.O>[ClH:41].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:38][CH2:39][OH:40])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: OCCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 345 mg, 0.80 mmol) was dissolved in dimethylformamide (3 ml) and potassium carbonate (331 mg, 2.40 mmol) added. This was stirred for 5 minutes at room temperature then 2-bromoethanol (0.086 ml, 1.21 mmol) added and the reaction mixture heated for 5 days at 60° C. Only a small amount of starting material had converted to product so a further 25 equivalents of 2-bromoethanol (1.42 ml, 20 mmol) was added and the temperature increased to 80° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [5%-20% ethyl acetate in iso-hexane] to give a yellow oil and the hydrochloride salt was made by adding 1 equivalent of hydrogen chloride in diethyl ether (1N). The title compound was filtered off and dried at 60° C. in vacuo.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:31][CH2:27][CH2:28][CH2:29][CH3:30])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCCN
Solvent: CC#N
Product: CCCCNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.018 g, 0.046 mmol), butan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 6), 256 (5), 87 (6), 86 (bp), 70 (5).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.Cl.O>C1COCC1.CCOC(C)=O>[N+:11]([C:7]1[CH:6]=[C:5]([CH2:4][CH:3]=[O:2])[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: COC=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=CCc1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
To a solution of 1-(2-methoxyvinyl)-3-nitrobenzene (1.8 g, 10.06 mmol) in THF (60 mL), was added 6N HCl (6.03 mL) and the mixture was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvents were evaporated under reduced pressure to afford a solid. The solid was dissolved in EtOAc (45 mL) and water (50 mL) was added and the mixture stirred for 15 minutes. The separated aqueous phase was extracted with EtOAc (30 mL), and then the combined organic extracts were washed with 5% sodium bicarbonate (25 mL), brine (30 mL), dried (Na2SO4) and the solvents removed under reduced pressure. The crude compound was purified by column chromatography on neutral silica gel using 15-20% EtOAc in hexane to afford the title compound (1.2 g, 90%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8]/[C:7](=[N:32]\[OH:33])/[C@H:6]1[O:34]C(=O)C)(=O)C.N>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:9]2[O:8][C:7](=[N:32][OH:33])[C@@H:6]([OH:34])[C@H:5]([OH:4])[C@H:10]2[OH:11])=[CH:16][C:17]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O/C(=N\O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: N
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC(=NO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Yield: 77.8 %

Procedure:
Compound from step B (97 mg, 0.18 mmol) was treated with 7.0 M NH3 in MeOH (1.8 ml) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by flash chromatography (12 g SiO2, 0-12% MeOH:CH2Cl2), suspended in H2O, and lyophilized to give (3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-one oxime (57 mg, 0.14 mmol, 77%) as a white solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[C:25]=1[C:31]#[N:32])=[O:22]>C1COCC1>[CH3:29][N:28]1[C:24]2[NH:23][C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][NH:32][C:31]=3[C:25]=2[C:26]([CH3:30])=[N:27]1
Reactant: Cc1nn(C)c(NC(=O)CCCCCl)c1C#N
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nn(C)c2[nH]c(=O)c3c(c12)NCCC3
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2,2,6,6-tetramethylpiperidine (1.66 mL, 9.8 mmol) in anhydrous THF (20 mL) was added n-butyllithium (2.5 M solution in hexane, 3.92 mL, 9.8 mmol) at −20° C. The solution was stirred at −20° C. for 30 min, and a solution of Example 96A (1.0 g, 3.92 mmol) in 10 mL of anhydrous THF was added dropwise. The resulting dark red mixture was stirred at the same temperature for 30 min. The reaction was quenched with water, and the mixture was concentrated. The residue was partitioned between ethyl acetate and brine. The formed solid material in the bi-phase mixture was collected by filtration, washed with EtOAc and water. The obtained crude product was recrystallized from methanol to give Example 96. Yield: 343 mg (40%). MS (DCI): m/z 219 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.71-1.79 (m, 2H), 2.33-2.37 (m, 5H), 3.20-3.25 (m, 2H), 3.65 (s, 3H), 6.04 (br s, 1H), 11.06 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[CH:10]=1)=[S:7].ClC(Cl)(Cl)Cl.BrBr>C(#N)C>[CH2:15]([C:11]1[CH:12]=[CH:13][C:14]2[S:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:8][C:9]=2[CH:10]=1)[CH2:16][CH3:17]
Reactant: CCCc1cccc(NC(=S)NCCCO)c1
Agent: BrBr
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1ccc2sc(NCCCO)nc2c1

Procedure:
To a stirred mixture of 27.7 parts of N-(3-hydroxypropyl)-N'-(3-propylphenyl)thiourea and 240 parts of tetrachloromethane are added 17.6 parts of bromine and the whole is stirred and refluxed for 1 hours. About 80 parts of acetonitrile are added and the formed hydrobromide salt is allowed to crystallize. It is filtered off, washed with acetonitrile and dissolved in water. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated, yielding 18 parts of 3-(5-propyl-2-benzothiazolylamino)-1-propanol as an oily residue.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)=CC=1>>[CH:25]1([CH2:24][CH2:23][O:12][C:9]2[CH:10]=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCCC2)cc1
Reactant: COC(=O)c1cc(O)ccc1O
Product: COC(=O)c1cc(OCCC2CCCCC2)ccc1O
Yield: 43 %

Procedure:
Synthesis was carried out in the same manner as in Example 1, except for replacing methyl 2,4-dihydroxybenzoate with methyl 2,5-dihydroxybenzoate and replacing 2-ethylhexyl bromide with 2-cyclohexylethyl p-toluenesulfonate, to obtain methyl 5-(2-cyclohexylethoxy)-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 11) as a pale yellow solid in a yield of 43%. The analytical results are shown below. ##STR32##
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)O[C:15](=[O:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-:5])=[O:4]>C1COCC1.CC(O)=O>[CH3:1][N:2]1[C:15](=[O:16])[C:10]2[C:11](=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][CH:9]=2)[N:12]=[C:13]1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A solution of methylamine (6.3 mL, 12.5 mmol) in THF was added to a suspension of 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one 3 (1.5 g, 4.2 mmol) in AcOH (18 mL). The reaction mixture was heated under gentle reflux for 12 h then cooled to room temperature. The volatiles were removed in vacuo and the residue was taken up in EtOAc, washed with sat. aq NaHCO3, brine, dried (MgSO4) and concentrated. The residue was purified by MPLC eluting with pentane/EtOAc (0-75%) to give 4 (1.3 g, 89% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.C(OCC)(=O)C(OCC)=O.C(OC(=O)C(=O)CC(=O)COC1C=CC=CC=1)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:64]1[N:65]([CH2:77][CH:78]([NH:80][C:81](OC(C)(C)C)=O)C)[N:66]=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:64]3[CH2:81][NH:80][CH2:78][CH2:77][N:65]3[N:66]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Reactant: CC(=O)COc1ccc(F)cc1
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Solvent: CCOC(=O)C(=O)OCC
Product: Fc1ccc(OCc2cc3n(n2)CCNC3)cc1

Procedure:
The compound was prepared from 1-(4-fluoro-phenoxy)-propan-2-one and diethyl oxalate using the methods described in the preceding examples 9 (2,4-dioxo-5-phenoxy-pentanoic acid ethyl ester), 10 (5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[S:30](Cl)(=[O:32])=[O:31]>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccco1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and furan-2-sulfonyl chloride (72 mg, 0.437 mmol), the title compound was obtained as a white solid (87 mg, 63% yield). MS (ESI): 474 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[OH-].[NH4+:27]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([CH3:22])([CH3:21])[C:18]([NH2:27])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C(=O)Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C(N)=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoyl chloride in THF (3 mL) was added ammonium hydroxide (10 mL). The reaction was stirred overnight at ambient temperature. The reaction mixture was concentrated onto silica and purification (FCC, SiO2, 0-10%, MeOH/DCM) afforded the title compound as a white solid (28 mg, 10%). 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=2.7 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.39-7.27 (m, 4H), 5.34-5.22 (m, 2H), 5.19 (s, 2H), 1.71 (s, 6H). [M+H]=355.3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1.[BH4-].[Na+]>C1COCC1.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)[OH:20])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 88.3 %

Procedure:
To a solution of bis(4(2-quinolylmethoxy)phenyl ketone (1.25 g, 2.5 mmol), prepared as in step 1, in THF/CH3OH (1:1, 60 mL) at room temperature was added NaBH4 (0.37 g, 10 mmol) and the mixture was refluxed for 3 hours, concentrated in vacuo, suspended in water and neutralized with citric acid. The resulting precipitate was collected by filtration, washed with 20% Et2O/hexane and dried in vacuo to afford bis(4-(2-quinolylmethoxy)phenyl)methanol (1.1 g, 88%) as white solid.
Reaction SMILES: [OH:1][C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)=[O:13])[CH2:5][CH2:4]1.[BH4-].[Na+]>CO>[OH:1][C:2]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[OH:13])[CH2:5][CH2:4]1
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetic acid, prepared in accordance with Example 12, and 300 mg of NaBH4 in 25 mL of CH3OH was stirred overnight at room temperature. The mixture was then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous portion was treated with concentrated HCl until pH 6, then extracted with EtOAc. The organics were concentrated in vacuo. The residue was dissolved in EtOAc, filtered, and concentrated in vacuo to an oil. The oil was dissolved in CH3OH and concentrated to a solid. The solid was slurried with EtOAc, filtered, and rinsed with EtOAc to afford 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24](O)=[C:23]([CH3:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:24]2[CH:25]=[CH:26][C:21]([C:20]([O:19][CH3:18])=[O:29])=[CH:22][C:23]=2[CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 0 °C
Yield: 53 %

Procedure:
4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester from Example E68.1 (400 mg, 1.64 mmol) and 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (274 mg, 1.64 mmol) were dissolved in THF (30 ml) and cooled down to 0° C. Polymer-supported triphenyl-phosphine (1.7 g, 2.46 mmol) then DEAD (0.387 ml, 2.46 mmol) were added and the mixture was heated at re-flux for 20 h. The resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 20% EtOAC:80% cyclohexane) to yield the title compound (340 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:28]=2)[CH2:19][CH2:18]1>>[F:35][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH3:12])[CH2:22][CH2:21]2)=[CH:28][C:27]=1[NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33]
Reactant: CC(C(=O)O)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 46 was prepared from 2-(4-fluoro phenyl)propanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.38–8.23 (m, 1H), 7.48–7.27 (m, 3H), 7.13–6.94 (m, 4H), 6.94–6.82 (m, 1H), 3.62–3.46 (m, 1H), 3.41–3.26 (m, 2H), 3.17–3.03 (m, 1H), 3.02–2.91 (m, 1H), 2.67–2.35 (m, 4H), 2.24–1.97 (m, 2H), 1.95–1.62 (m, 6H), 1.49 (d, 3H, J=7.2 Hz), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 472.4 (M+H)+.